S1p3 antagonists

ABSTRACT

The present invention relates to antagonists of the S1P3 receptor formula (A) as herein described and pharmaceutical compositions thereof. The compounds of formula (A) are useful in the preparation of a medicament, in particular for the treatment of Alzheimer&#39;s disease.

The present invention relates to novel antagonists of the S1P3 receptorof formula (A) as herein described and to their pharmaceutical uses.

Such antagonists can be used for the treatment of inflammation-relateddiseases such as arthritis, fibrosis, inflammatory syndromes,atherosclerosis, vascular diseases, asthma, bradycardia, acute lunginjury, lung inflammation, cancer, ocular hypertension, glaucoma,neuroinflammatory diseases, Sandhoff's disease, kidneyischemia-reperfusion injury, pain, diabetic heart disease andneurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, Amyotrophic lateral sclerosis, Huntington's disease or MultipleSclerosis.

BACKGROUND OF THE INVENTION

The S1P3 receptor gene encodes for a member of the endothelialdifferentiation gene (EDG) family of receptors widely present in centraland peripheral human tissues (Rosen et al., 2009; Ishii et al., 2001).S1P₃ receptor (also called: EDG3; LPB3; S1PR3; EDG-3) belong to a classof five (S1P₁₋₅) seven-spanning membrane proteins belonging to the classof G-Protein-Coupled Receptors (GPCRs), whose natural ligand is thebioactive lipid sphingosine-1-phosphate (S1P) (Chun et al., 2002). S1Pis involved in a large array of cellular responses modulating severalphysiological processes such as innate immunity, wound healing, vascularendothelial cell functions, inflammatory response and others (Ishii etal., 2004; Brinkmann, 2007; Rosen et al., 2009; Maceyka et al., 2012).S1P is intracellularly produced, with the direct role of secondarymessenger (Spiegel and Milstien, 2003), and extracellularly exportedacting to S1P cell membrane receptors as endogenous ligand.

The S1P receptors expressed in many apparatuses are able to triggersignalling through a variety of heterotrimeric G proteins, includingGi/o, G12/13, and Gq. In the S1P₁₋₅ receptors family, S1P₃ has beenshown to be functionally relevant in several physiological processessuch as regulations of heart rate, angiogenesis and vascular contraction(Forrest et al., 2004; Sanna et al., 2004; Marsolais and Rosen, 2009;Means and Brown, 2009; Murakami et al., 2010), in embryonic angiogenesisdevelopment (Kono et al., 2004) or as autophagy modulator (Taniguchi etal., 2012). The S1P₃ receptor is also deeply involved in immunologicalprocesses (Brinkmann V. (2009). Importantly, mice lacking S1 P₃ receptordid not show evident abnormalities indicating a non-essential role ofthe receptor for a normal animal development (Ishii et al., 2001). Asmentioned, S1P plays an important role as essential modulator of innateimmunity and inflammation inducer. S1P once produced and released assignalling molecule by a wide range of cell types or even non-nucleatedcells (e.g. platelets) (Pyne and Pyne, 2000) can exert an important rolein inflammation. As introduced, together with the whole S1P receptorfamily, S1P₃ receptor system has been largely studied focusing on itsrole in disease and has been shown to be involved in a large number ofpathologies. From the literature S1P₃ emerges as an important targetimplicated in pathologies with inflammatory components, in this case apharmacological inhibition of the receptor could potentially counteractthe disease evolution. The S1 P₃ receptor appears to be an appealingtarget also for other therapeutic areas, in which a potential healingrole of S1P₃ antagonism has been demonstrated.

S1P₃ Antagonism in Peripheral Diseases

S1 P₃ activity has been shown to be implicated ininflammation-associated diseases such as arthritis (Lai et al., 2010),and several type of fibrosis (Shea and Tager, 2012) like heart (Takuwaet al., 2010), pulmonary (Kono et al., 2007), muscular (Cencetti et al.,2008) and liver fibrosis (Li et al., 2009) or in other more generalinflammatory syndromes (Niessen et al., 2008) where S1P₃ receptorantagonism could potentially limit the pathologic processes.

S1 P₃ receptor activation in the cardiovascular system could exertseveral pathologically-relevant effects. In the blood the S1P releasedby activated platelets stimulates S1P₃ (and S1P₁) receptors in vascularendothelium decreasing vascular para-cellular permeability (Mehta et al.2005; Sun et al. 2009). Additionally, S1P₃ transactivation has beenshown to disrupt vascular barrier regulation (Singleton et al., 2006).Furthermore, also the chemotactic effect of S1P in macrophages(demonstrated in vitro and in vivo) is mediated by S1P₃, so playing acausal role in atherosclerosis by promoting the recruitment ofinflammatory monocyte/macrophage and altering vessel smooth muscle cellsbehaviour (Keul et al., 2011). Finally, the group of Takakura hasdemonstrated by a specific antagonist that the S1P-induced coronary flowdecrease is dependent on S1P₃ receptor and so such antagonism might beadapt to counteract S1P related vascular diseases and vasospasmsyndromes (Murakami et al., 2010). In the heart, interestingly, thesustained bradycardia induced by S1P receptor non-selective agonists isabolished in S1P₃ knockout mice or after S1P₃ pharmacological inhibitionin rats (Sanna et al., 2004; Murakami et al., 2010). More, in thecardiac vascular microcirculation cells in diabetes, it has been shownin vivo and in vitro that the agonist FTY720 exerts a functionalantagonism by stimulating the translocation of S1P₃ from membrane to thenucleus. Arguably, the pharmacological modulation of S1P₃ receptorscould be beneficial to alleviate cardiac microangiopathy in diabetes(Yin et al., 2012).

Bajwa et al. (2012) have demonstrated that S1P plays a pivotal role inkidney ischemia-reperfusion injury (IRI). S1P₃ receptor-deficient micewere protected from IRI. This protective effect was due, at least inpart to differences between S1P₃-deficient dendritic cells. It was thensupposed that pharmacological treatment are able to limit S1 P₃ activityor treatments with dendritic cells lacking the S1P₃ receptor could helpagainst progression of IRI.

Also several physiological parameters of the respiratory system areaffected by S1P₃ activity. It has been recently demonstrated that theS1P pathway activation induced a generalized airway hyperreactivity invivo and in vitro and this is mediated by S1 P₃ receptor. Then, the S1P₃ antagonism, besides or contextually to the abovementioned putativehealing effects on lung fibrosis, could represent a new therapeuticstrategy aimed at blocking the asthma-related airway hyperreactivity(Trifilieff and Fozard, 2012). S1P₃ has been also shown to be strictlyinvolved in acute lung injury where it promotes chemotaxis and increasedendothelial and epithelial permeability (Uhlig and Yang, 2013). In thepublication of Chen et al., (2008) it is suggested that S1P actingthrough S1P₃, increasing calcium influx, and Rho kinase, activatescPLA(2)alpha and releases arachidonic acid in lung epithelial cells.Then, understanding this mechanism in epithelial cells may providepotential targets to control inflammatory processes in the lung.

S1P₃ receptors play an important role in other non-inflammatorydiseases. In cancer, it has been shown that S1 P₃ activation promotesbreast cancer cells invasiveness (Kim et al., 2011) and this effect canbe diminished by a specific antibody able to block the receptor (Harriset al., 2012). Similar results were obtained in thyroid cancer cells(Balthasar et al., 2006) and glioma cells (Young et al., 2007), whereS1P₃ activation showed to enhance cell migration and invasion. Yamashita(2006) also demonstrated that S1P₃-mediated signals might be crucial indetermining the metastatic response of gastric cancer cells to S1P.

In the eye, considering that S1P is constitutively present in theaqueous humor (Liliom et al., 1998), and, in addition, that theendothelial cells of the trabecular meshwork, which express S1P₁ andS1P₃ receptors (Mettu et al., 2004), respond to S1P stimulus increasingthe outflow resistance, the S1P₃ receptors pharmacological inhibitionrepresents a potential therapeutic strategy in healing pathologiesinvolving high intraocular pressure such as ocular hypertension,glaucoma, glaucomatous retinopathy (Stamer et al., 2009).

S1P₃ antagonism in PNS diseases

The tissue injury inflammation is associated with an increasedsensitivity to noxious stimuli, suggesting that there could be animportant interaction between the activities of immune cells and thesensory neurons activated by noxious stimulation. A direct exposure ofisolated sensory neurons to S1P (together with other inflammatorysignals released by platelets or mast cells) increases their actionpotential firing through activation of ion channels (Zhang et al.,2006). In experimental conditions of isolated sensory neurons, theexpression of S1P₃ receptors is the highest in the panel of S1Preceptors. In addition, the Kress's laboratory has demonstrated thatS1P₃ receptor was detected in all human and mouse dorsal root ganglianeurons and that S1P evokes significant nociception viaG-protein-dependent activation of an excitatory chloride conductance(Camprubi-Robles et al., 2013). Considering that S1P-induced neuronalresponses and spontaneous pain behavior in vivo were strongly reduced inS1P₃-null mice, S1P₃ receptors could represent important therapeutictargets for post-traumatic pain (Camprubi-Robles et al., 2013).

S1P₃ Antagonism in CNS Diseases

In the CNS, neurons, astrocytes, oligodendrocytes and microglia cellshave the capacity to produce and secrete S1P and express, with differentextents depending on the cell type, S1P₁₋₃ and S1P₅ receptors (Anelli etal., 2005; Foster et al., 2007). In regard to S1P₃ receptor, anintrinsic high expression has been seen in both astrocytes and neurons(Foster et al., 2007). S1P₃ is described to induce glial activationunder pro-inflammatory conditions (Fisher et al., 2011; Wu et al., 2008)and enhance spontaneous glutamate release in the hippocampus mossyfibers (Kanno and Nishizaki, 2011). In particular, apoptotic neuronsself-induce an overexpression of sphingosine-kinase with a furtherrelease of S1P. This process, elegantly demonstrated by Gude (Gude etal., 2008) and defined as “come-and-get-me” signal, has the purpose ofchemo-attract microglial cells and eliminate the dying neuron.Furthermore, S1P through a G12/13 protein, by remodelling of actincytoskeleton, can inhibit astrocytes tight junction, conferring themmobility, and creating gaps through the brain tissue (Rouach et al.,2006). Then, the action of S1P to astrocytes could help the activatedmicroglial cells to better move in the brain and so express theirphagocytic role. The S1P₃ receptors coupling to the G12/13 protein,associated to a high S1P₃ receptor expression in astrocytes and its rolein motility (Fischer et al., 2011) leaded to the consideration that thedescribed process could be conducted by a S1P₃-activated signalling.Interestingly, microglial cells, once activated, enhance their S1P₃expression (Foster et al., 2007). With these evidences it wasconceivably hypothesised that activation of S1P₃ receptor system isstrictly involved in a neuroinflammatory state and S1P₃ inhibition couldhave limited its development. Evidence supporting S1 P₃ antagonism to beprotective in neuroinflammation was given from a mouse model of Sandhoffdisease in which the ablation of the gene encoding S1 P₃ receptorstrongly limited the astroglial proliferation, prolonging the survivaland improving motor function of the mice (Wu et al., 2008).

In neurodegenerative diseases neuroinflammation can play a cleardetrimental role during the pathologic evolution Alzheimer's,Parkinson's, Amyotrophic lateral sclerosis, Huntington and Multiplesclerosis (Bradl and Hohlfeld, 2003; Maragakis and Rothstein, 2006;Davies et al., 2013). In Alzheimer disease (AD) the accumulation ofbeta-amyloid plaques has been associated to inflammation developmentwith activation of the CNS immune system (Meraz-Rios et al., 2013). Arelevance of S1P receptors activity and modulation in AD is also shownin Takasugi et al., 2011 and in Takasugi et al., 2013

PRIOR ART

EP81756 discloses compounds that are useful for treating inflammation.

Wang et al. (Bioorganic & Medicinal Chemistry Letters (2010), 20(2),493-498) disclose compounds that are FFA2 inhibitors useful for thetreatment of diabetes.

WO2000026202 discloses antiproliferative compounds that are useful forthe treatment of cancer.

WO2003063797 discloses potassium channel inhibitors that are useful forthe treatment of arrhythmia.

JP2002155065 discloses compounds that are useful as insecticides ormiticides.

WO2001036415 discloses compounds that are useful for controlling pestson domestic animals and livestock.

In WO2005075435, WO2007087066, WO2008141119, WO2008147797, WO2009006315,WO2009123896 and WO2010054138, Vertex discloses compounds as CFTRmodulators for the treatment of cystic fibrosis or as intermediatestowards such compounds.

Ingyong Huaxue (1990), 7(6), 54-7 discloses pesticides and fungicides.

The following disclose activators of glucokinase useful for thetreatment of diabetes: Journal of Medicinal Chemistry (2012), 55(3),1318-1333; WO2009140624; US-20100063063; Journal of Medicinal Chemistry(2012), 55(16), 7021-7036; Medicinal Chemistry Letters (2013), 4(4),414-418; US-20010039344; WO2001083465; WO2003095438; WO2004052869;WO2006058923; WO2007026761; WO2007041365; WO2008005914; WO2008078674;WO2008119734; WO2009091014; U.S. Pat. No. 6,610,846; Journal ofMedicinal Chemistry (2010), 53(9), 3618-3625; WO2002046173;US20070281942; US2010063063.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Neuroprotective effect of a compound of the invention onquisqualic acid lesioned rats. Example 33 shows strong neuroprotectiveeffects at 30 and 60 mg/Kg/day. Rat NBM ChAT-positive neuron countsusing APERIO® (left), example 33 at doses of 30 and 60 mg/kg wasadministered once a day p.o.; the dose of 10 mg/kg was administered p.o.twice a day. In the microphotographs (right panel) a ChAT-qualitativeanalysis is shown in Quisqualic acid (QUIS) or Sham (SHAM)-injected ratNBM treated with vehicle or example 33 at 30 mg/kg p.o. *p<0.05 vs SHAM(Dunnet Test).

FIG. 2: Anti-neuroinflammatory effect of a compound on quisqualic acidlesioned rats. Example 33 has a strong activity on GFAP reactivity at 30and 60 mg/Kg/day. A) effect on microglia cells, OX42 analysis; B) effecton astrocytes, GFAP analysis. These evidences are in line with theliterature, in which the expression of S1P3 on microglia is consideredlow and not relevant (S1P2 is predominant), while the receptor appearsto be highly expressed in astrocytes.

FIG. 3: Effect of a compound of the invention on Abeta(25-35) lesionedrats. Microscope scanning (GFAP staining) A) Ab (23-35) (righthemisphere)+Vehicle B) Ab(25-35) (right hemisphere)—example 33 at 30mg/kg (left hemisphere was Sham-treated). C) quantitative analysis ofGFAP-positive cells by visual scoring (*p<0.05 vs vehicle group,Kruskall-Wallis).

FIG. 4: Effect of a compound of the invention in the Object RecognitionTest on quisqualic acid lesioned rats. Treatment with example 33significantly ameliorates cognitive functions in ORT measuring episodicmemory in Quisqualic lesioned rats as reported in the table of ANOVA(right panel). To note the difference in the exploration time betweenfamiliar and novel objects (F=familiar object, N=novel object).

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect of this invention (embodiment A), there is providedcompounds of formula (A),

wherein

—R₁ is

X₁, X₆, X₇, X₉ and X₁₀ are halogen, C₁-C₄ linear branched or cyclicalkyl optionally substituted with one or more fluorine atoms;X₂, X₃, X₄, X₅ and X₈, are hydrogen, halogen, C₁-C₄ linear branched orcyclic alkyl optionally substituted with one or more fluorine atoms;with the proviso that at least one of X₂, X₃, X₄, and X₅ is nothydrogen;R₂ is a C₃-C₆ linear branched or cyclic alkyl optionally substitutedwith phenyl, with one or more fluorine atoms or withtrifluoromethyl-furanyl;R₂′ is hydrogen, F, C₁-C₃ linear or branched alkyl optionallysubstituted with one or more fluorine atoms;or R₂ and R₂′ together with the carbon atom they are attached to form aC₃-C₆ cycloalkyl ring;

—R₃ is

Y₁ is halogen;Y₁′ is C₁-C₃ linear branched or cyclic alkyl optionally substituted withone or more fluorine atoms;Y₂ is cyano or methoxyphenyl, C₁-C₃ linear branched or cyclic alkyloptionally substituted with one or more fluorine atoms;Y₃ is hydrogen, halogen or methoxyphenyl;Y₄ is hydrogen, halogen, N-methylpyrazolyl or a C₁-C₃ linear branched orcyclic alkoxy optionally substituted with one or more fluorine atoms,Y₅ is hydrogen, halogen, cyano, or a C₁-C₃ linear branched or cyclicalkyl optionally substituted with one or more fluorine atoms;with the proviso that at least one of Y₄ and Y₅ is not hydrogen;Y₆ is halogen, C₁-C₃ linear branched or cyclic alkyl optionallysubstituted with one or more fluorine atoms, or a C₁-C₃ linear branchedor cyclic alkoxy optionally substituted with one or more fluorine atoms;enantiomers, enantiomerically enriched mixtures, and pharmaceuticallyacceptable salts thereof.Under one aspect of embodiment A (embodiment A1), there is providedcompounds of formula (A) wherein halogen is selected from the list ofCl, Br and F;C₁-C₄ linear branched or cyclic alkyl optionally substituted with one ormore fluorine atoms is selected from the list of methyl,trifluoromethyl, n-propyl and t-butyl;C₁-C₃ linear branched or cyclic alkyl optionally substituted with one ormore fluorine atoms is selected from the list of methyl, trifluoromethyland n-propyl; C₁-C₃ linear branched or cyclic alkoxy optionallysubstituted with one or more fluorine atoms is selected from the list ofmethoxy and difluoromethoxy;C₃-C₆ linear branched or cyclic alkyl optionally substituted withphenyl, with one or more fluorine atoms or with trifluoromethyl-furanylis selected from n-propyl,3-phenyl-n-propyl i-propyl, n-butyl,cyclohexyl and (5-trifluoromethyl-furan-2yl)-methyl; C₃-C₆ cycloalkyl isselected from the list of cyclobutyl and cyclopentyl;

Under another aspect of embodiment A (embodiment A2), there is providedcompounds of formula (A) wherein halogen is selected from the list ofCl, Br and F; C₁-C₄ linear branched or cyclic alkyl optionallysubstituted with one or more fluorine atoms is selected from the list ofmethyl, trifluoromethyl and t-butyl; C₁-C₃ linear branched or cyclicalkyl optionally substituted with one or more fluorine atoms is selectedfrom the list methyl and trifluoromethyl;

C₁-C₃ linear branched or cyclic alkoxy optionally substituted with oneor more fluorine atoms is selected from the list of methoxy anddifluoromethoxy;C₃-C₆ linear branched or cyclic alkyl optionally substituted withphenyl, with one or more fluorine atoms or with trifluoromethyl-furanylis selected from n-propyl,3-phenyl-n-propyl i-propyl, n-butyl,cyclohexyl and (5-trifluoromethyl-furan-2yl)-methyl;C₃-C₆ cycloalkyl is selected from list of cyclobutyl and cyclopentyl;Under another aspect of embodiment A (embodiment A3), there is providedcompounds of formula (A) wherein R₁ and R₃ are as described underembodiment A and whereinX₁ is halogenX₂ is hydrogen, halogen or methylX₃ is hydrogen, halogen or trifluoromethylX₄ is hydrogen or methylX₅ is hydrogen or halogenwith the proviso that at least one of X₂, X₃, X₄, and X₅ is not hydrogenX₆ is halogenX₇ is t-butyl or trifluoromethyl, preferably t-butylX₈ is hydrogen, methyl or t-butylX₉ is halogenX₁₀ is t-butylR₂ is n-propyl, 3-phenyl-n-propyl, i-propyl, n-butyl, cyclohexyl or(5-trifluoromethyl-furan-2yl)-methylR₂′ is hydrogen, F, methylor R₂ and R₂′ together with the carbon atom they are attached to form acyclobutyl or cyclopentyl ring;Y₁ is halogenY₁′ is methylY₂ is methyl, n-propyl, cyano, trifluoromethyl or 4-methoxyphenylY₃ is hydrogen, halogen, or 4-methoxyphenylY₄ is hydrogen, halogen, methoxy or 1-methyl-pyrazol-4-ylY₅ is hydrogen, halogen, cyano or methylwith the proviso that at least one of Y₄ and Y₅ is not hydrogen Y₆halogen, methoxy or difluoromethoxyUnder another aspect of embodiment A (embodiment A4), there is providedcompounds of formula (A) wherein R₁ and R₃ are as described underembodiment A andwherein

X₁ is Cl or Br

X₂ is hydrogen, methyl, Br or FX₃ is hydrogen, Br, Cl, F, or trifluoromethylX₄ is hydrogen or methylX₅ is hydrogen or F with the proviso that at least one of X₂, X₃, X₄,and X₅ is not hydrogen

X₆ is Cl

X₇ is t-butyl or trifluoromethyl, preferably t-butylX₈ is hydrogen, methyl or t-butyl

X₉ is Br, Cl or F

X₁₀ is t-butylR₂ is n-propyl, 3-phenyl-n-propyl, i-propyl, n-butyl, cyclohexyl or(5-trifluoromethyl-furan-2yl)-methyl;R₂′ is hydrogen, F, methyl;or R₂ and R₂′ together with the carbon atom they are attached to form acyclobutyl or cyclopentyl ring;

Y₁ is Br

Y₁′ is methylY₂ is methyl, n-propyl, cyano, trifluoromethyl and 4-methoxyphenylY₃ is hydrogen, Br, Cl, and 4-methoxyphenylY₄ is hydrogen, Br, Cl, methoxy or 1-methyl-pyrazol-4-ylY₅ is hydrogen, Br, Cl, F, cyano or methyl with the proviso that atleast one of Y₄ and Y₅ is not hydrogenY₆ is Br, Cl, F, methoxy or difluoromethoxy

Under specific aspects of embodiments A, A1, A2, A3 or A4 (embodimentsB1) there is provided compounds of formula (A) wherein —R₁ is selectedfrom

and wherein R₂, R₂′, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁,Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as the case may be, as defined underembodiment A, A1, A2, A3 or A4

Under specific aspects of embodiments A, A1, A2, A3 or A4 (embodimentsB2) there is provided compounds of formula (A) wherein —R₁ is selectedfrom

and wherein R₂, R₂′, R₃, X₇, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as thecase may be, as defined under embodiment A, A1, A2, A3 or A4

Under specific aspects of embodiments A, A1, A2, A3 or A4 (embodimentsB3) there is provided compounds of formula (A) wherein —R₁ is selectedfrom

and wherein R₂, R₂′, R₃, X₁, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as thecase may be, as defined under embodiment A, A1, A2, A3 or A4

Under specific aspects of embodiments A, A1, A2, A3 or A4 (embodimentsB4) there is provided compounds of formula (A) wherein —R₁ is selectedfrom

and wherein R₂, R₂′, R₃, X₂, X₃, X₄, X₅, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆are, as the case may be, as defined under embodiment A, A1, A2, A3 or A4

Under a particular aspect of embodiments B4 (embodiments B4a), there isprovided compounds of formula (A) wherein X₂ and X₄ are hydrogen andwherein R₁, R₂, R₂′, R₃, X₃, X₅, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, asthe case may be, as defined under embodiments B4.

Under another particular aspect of embodiments B4 (embodiments B4b),there is provided compounds of formula (A) wherein X₂, X₄ and X₅ arehydrogen and wherein R₁, R₂, R₂, R₃, X₃, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆are, as the case may be, as defined under embodiments B4.

Under specific aspects of embodiments A, A1, A2, A3 or A4 (embodimentsB5) there is provided compounds of formula (A) wherein —R₁ is selectedfrom

and wherein R₂, R₂′, R₃, X₆, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as thecase may be, as defined under embodiment A, A1, A2, A3 or A4

Under specific aspects of embodiments A, A1, A2, A3 or A4 (embodimentsB6) there is provided compounds of formula (A) wherein —R₁ is selectedfrom

and wherein R₂, R₂′, R₃, X₇, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as thecase may be, as defined under embodiment A, A1, A2, A3 or A4

Under specific aspects of embodiments A, A1, A2, A3 or A4 (embodimentsB7) there is provided compounds of formula (A) wherein —R₁ is selectedfrom

and wherein R₂, R₂′, R₃, X₈, X₉, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, asthe case may be, as defined under embodiment A, A1, A2, A3 or A4

Under specific aspects of embodiments A, A1, A2, A3 or A4 (embodimentsB8) there is provided compounds of formula (A) wherein —R₁ is selectedfrom

and wherein R₂, R₂′, R₃, X₁₀, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as thecase may be, as defined under embodiment A, A1, A2, A3 or A4

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C1) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁,Y₂, and Y₃ are, as the case may be, as defined under embodiments A, A1,A2, A3, A4, B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C2) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁,Y₄, Y₅, and Y₆ are, as the case may be, as defined under embodiments A,A1, A2, A3, A4, B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C3) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁,Y₁′, Y₄, Y₅, and Y₆ are, as the case may be, as defined underembodiments A, A1, A2, A3, A4, B1, B2, B3, B4, B4a, B4b, B5, B6, B7 orB8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C4) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀ and Y₁are, as the case may be, as defined under embodiments A, A1, A2, A3, A4,B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C5) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀ and Y₁are, as the case may be, as defined under embodiments A, A1, A2, A3, A4,B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C6) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂′, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₂and Y₃ are, as the case may be, as defined under embodiments A, A1, A2,A3, A4, B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C7) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂′, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀ and Y₁are, as the case may be, as defined under embodiments A, A1, A2, A3, A4,B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C8) there is provided compoundsof formula (A)

wherein —R₃ is selected from and wherein R₁, R₂, R₂′, X₁, X₂′, X₃, X₄,X₅, X₆, X₇, X₈, X₉, X₁₀ and Y₄ and Y₅ are, as the case may be, asdefined under embodiments A, A1, A2, A3, A4, B1, B2, B3, B4, B4a, B4b,B5, B6, B7 or B8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C9) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂′, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀ and Y₆are, as the case may be, as defined under embodiments A, A1, A2, A3, A4,B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 or B8 (embodiments C10) there is provided compoundsof formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂′, X₃, X₄, X₅, X₆, X₇, X₈, X₉ and X₁₀are, as the case may be, as defined under embodiments A, A1, A2, A3, A4,B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8.

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7 and B8 (embodiments C11) there is providedcompounds of formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂′, X₃, X₄, X₅, X₆, X₇, X₈, X₉ and X₁₀are, as the case may be, as defined under embodiments A, A1, A2, A3, A4,B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8.

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7, B8, C1, C2, C3, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀ andC₁₁ (embodiments D1) there is provided compounds of formula (A) whereinR₂ and R₂′ do not form a cycloalkyl ring together with the carbon atomthey are attached to.

and wherein R₁, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁, Y₁′,Y₂, Y₃, Y₄, Y₅ and Y₆ are, as the case may be, as defined underembodiments A, A1, A2, A3, A4, B1, B2, B3, B4, B4a, B4b, B5, B6, B7, B8,C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 or C11.

Under particular aspects of embodiments D1 (embodiments D1a), there isprovided compounds of formula (A) wherein R₂′ is hydrogen and whereinR₁, R₂, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁, Y₁′, Y₂, Y₃,Y₄, Y₅ and Y₆ are, as the case may be, as defined under embodiments D1.

Under other particular aspects of embodiments D1 (embodiments D1b),there is provided compounds of formula (A) wherein R₂′ is F and whereinR₁, R₂, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁, Y₁′, Y₂, Y₃,Y₄, Y₅ and Y₆ are, as the case may be, as defined under embodiments D1.

Under another particular aspect of embodiments D1 (embodiments D1c),there is provided compounds of formula (A) wherein R₂′ is different fromhydrogen or F and wherein R₁, R₂, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈,X₉, X₁₀, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as the case may be, asdefined under embodiments D.

Under specific aspect of embodiments D1a, D1b and D1c (embodiments Did),there is provided compounds of formula (A) wherein R₂ is n-propyl andwherein R₁, R₂′, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁, Y₁′,Y₂, Y₃, Y₄, Y₅ and Y₆ are, as the case may be, as defined underembodiments D1a, D1b and D1c.

Under specific aspect of embodiments D1a, D1b and D1c (embodiments D1e),there is provided compounds of formula (A) wherein R₂ is i-propyl andwherein R₁, R₂′, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁, Y₁′,Y₂, Y₃, Y₄, Y₅ and Y₆ are, as the case may be, as defined underembodiments D1a, D1b and D1c.

Under specific aspect of embodiments D1a, D1b and D1 c (embodimentsD1f), there is provided compounds of formula (A) wherein R₂ is n-butyland wherein R₁, R₂′, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁,Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as the case may be, as defined underembodiments D1a, D1b and D1c.

Under specific aspect of embodiments D1a, D1b and D1 c (embodiments D1f), there is provided compounds of formula (A) wherein R₂ is cyclohexyland wherein R₁, R₂′, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₁,Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as the case may be, as defined underembodiments D1a, D1b and D1c.

Under specific aspects of embodiments A, A1, A2, A3, A4, B1, B2, B3, B4,B4a, B4b, B5, B6, B7, B8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 andC11 (embodiments D2) there is provided compounds of formula (A) whereinR₂ and R₂′ together with the carbon atom they are attached to form acycloalkyl ring and wherein R₁, R₃, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉,X₁₀, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are, as the case may be, as definedunder embodiments A, A1, A2, A3, A4, B1, B2, B3, B4, B4a, B4b, B5, B6,B7, B8, C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 and C11.

The combination of any of the above embodiments gives rise to a newembodiment under this invention.

For example, from the combination of embodiments B3, B4 and B7 there isprovided other specific aspects of embodiments A, A1, A2, A3 or A4(Embodiments E1) which are compounds of formula (A) wherein —R₁ isselected from

and wherein R₂, R₂′, R₃, X₁, X₂, X₃, X₄, X₅, X₈, X₉, Y₁, Y₁′, Y₂, Y₃,Y₄, Y₅ and Y₆ are, as the case may be, as defined under embodiment A,A1, A2, A3 or A4

Likewise, from the combination of embodiments B3, B4a and B7, there isprovided other specific aspects of embodiments A, A1, A2, A3 or A4(Embodiments Ela) which are compounds of formula (A) wherein —R₁ isselected from

X₂ and X₄ are hydrogen;

and wherein R₂, R₂′, R₃, X₁, X₃, X₅, X₈, X₉, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ andY₆ are, as the case may be, as defined under embodiment A, A1, A2, A3 orA4

Also, from the combination of embodiments C6, C8, C9 and C11 there isprovided other specific aspects of embodiments A, A1, A2, A3, A4, B1,B2, B3, B4, B4a, B4b, B5, B6, B7 or B8 (Embodiments E2) which arecompounds of formula (A) wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₂,Y₃, Y₄, Y₅ and Y₆ are, as the case may be, as defined under embodimentsA, A1, A2, A3, A4, B1, B2, B3, B4, B4a, B4b, B5, B6, B7 or B8.

Examples 1-51 described below all constitute further individualembodiments of this invention, and any list combining any of theexamples is yet another further embodiment of this invention.

For example, in a further embodiment (embodiment F1) there is provided acompound selected form the list of

-   1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid    (5-chloro-pyridin-2-yl)-amide;-   2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid    (5-chloro-pyrazin-2-yl)-amide;-   2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(6-Bromo-pyridin-2-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(2-Bromo-pyridin-4-yl)-pentanoic acid    (5-bromo-pyridin-2-yl)-amide;-   2-(2-Methoxy-pyridin-4-yl)-pentanoic acid    (5-bromo-pyridin-2-yl)-amide;-   2-(6-Methoxy-pyridin-3-yl)-pentanoic acid    (5-bromo-pyridin-2-yl)-amide;-   2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(2-Difluoromethoxy-pyridin-4-yl)-pentanoic acid    (5-bromo-pyridin-2-yl)-amide;-   2-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid    (5-chloro-thiazol-2-yl)-amide;-   2-(5-Bromo-pyridin-3-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(5-Bromo-pyridin-3-yl)-pentanoic acid    (5-bromo-3-methyl-pyridin-2-yl)-amide;-   2-(5-Bromo-pyridin-3-yl)-pentanoic acid    (5-bromo-6-fluoro-pyridin-2-yl)-amide;-   2-(5-Bromo-pyridin-3-yl)-pentanoic acid    (5-chloro-pyrazin-2-yl)-amide;-   2-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic acid    (5-chloro-pyridin-2-yl)-amide;-   2-(2-Bromo-pyridin-4-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(2-Bromo-pyridin-4-yl)-pentanoic acid    (5-chloro-pyridin-2-yl)-amide;-   2-(5-Bromo-pyridin-3-yl)-pentanoic acid    (5-fluoro-pyridin-2-yl)-amide;-   2-(2-Methoxy-pyridin-4-yl)-pentanoic acid    (5-bromo-thiazol-2-yl)-amide;-   2-(2-Methoxy-pyridin-4-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid    (5-bromo-pyridin-2-yl)-amide;-   2-(4-Bromo-3-cyano-pyrazol-1-yl)-pentanoic acid    (5-bromo-pyridin-2-yl)-amide;-   2-(5-Bromo-pyridin-3-yl)-hexanoic acid (5-bromo-pyrazin-2-yl)-amide;-   2-(4-[4-methoxy-phenyl]-3-trifluoromethyl-pyrazol-1-yl)-pentanoic    acid (5-bromo-pyrazin-2-yl)-amide;-   2-(4-Bromo-3-methyl-pyrazol-1-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(4-Bromo-imidazol-1-yl)-pentanoic acid    (5-bromo-pyridin-2-yl)-amide;-   2-[3-(4-Methoxy-phenyl)-pyrazol-1-yl]-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(4-Bromo-3-cyano-pyrazol-1-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-[5-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic    acid (5-chloro-pyrazin-2-yl)-amide;-   2-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid    (5-chloro-pyrazin-2-yl)-amide;-   2-(5-Bromo-pyridin-3-yl)-N-(5-bromo-pyrazin-2-yl)3-methyl-butyramide;-   N-(5-Bromo-3-fluoro-pyridin-2-yl)-2-(5-bromo-pyridin-3-yl)-3-methyl-butyramide;-   N-(5-Bromo-pyrazin-2-yl)-2,2-dicyclohexyl-acetamide;-   1-(5-Bromo-pyridin-3-yl)-cyclobutanecarboxylic acid    (5-bromo-pyrazin-2-yl)-amide;-   1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide;-   2-(5-Chloro-pyridin-3-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)amide;-   2-(5-Chloro-pyridin-3-yl)-pentanoic acid    (5-chloro-pyrazin-2-yl)-amide;-   2-(6-Chloro-5-methyl-pyridin-3-yl)-pentanoic acid    (5-chloro-pyrazin-2-yl)-amide;-   and 2-(2-Chloro-pyridin-4-yl)-pentanoic acid    (5-bromo-pyrazin-2-yl)-amide

Likewise, in a in a further embodiment (embodiment F2) there is provideda compound selected form the list of 2-(5-Bromo-pyridin-3-yl)-pentanoicacid (3-tert-butyl-isoxazol-5-yl)-amide and2-(5-Bromo-pyridin-3-yl)-hexanoic acid(3-tert-butyl-isoxazol-5-yl)-amide

General Route to Compounds of the Invention

Depending on the exact nature of the compound, compounds of theinvention may be obtained under general Schemes 1-5.

A: carboxylation or Reformatsky-Negishi coupling; B: alkylation; C:miscellaneous modifications on final compounds; D: Hydrolysis; E: Amidecoupling between acid and amine; F: Amide coupling between ester andamine; G: esterification; H: alkylation on dicarbonyl compounds; I:alcoholysis; J: N-alkylation

Compounds with general structure I can be prepared as shown in Scheme 1.The key step of the synthesis is coupling between acids of generalstructure II and the appropriate amines of general structure III usingcoupling agents known in literature. Alternatively, amides of structureI can be achieved directly from esters IV where R2 is alkyl and R₂′ canbe fluorine or hydrogen. When acids of general structure II are notcommercially available, they can be prepared according to differentapproaches.

Alkylation of commercially available heteroarylacetic acid of generalstructure V, with the appropriate haloalkane, in presence of a strongbases such LiHMDS, n-butyllithium, sodium hydride and other known inliterature gives acids of general structure II.

When R₂ and R₂′ are different alkyl groups, acids of general structureII can be prepared in two steps. Heteroaryl acetic acids of generalstructure V can be alkylated to give intermediates of general structureVI, which undergo to a second alkylation to furnish acids of generalstructure II.

Alternatively commercially available heteroarylacetonitriles of generalstructure VII can be alkylated affording intermediates of generalstructure VIII which can be hydrolyzed to acids II.

Acids of general structure II can be obtained from hydrolysis of estersof general structure IV as reported in Scheme 1 where Pg can be methyl,ethyl or tert-butyl group. In case R₂′ is a cyano group, hydrolysis andmono-decarboxylation occur simultaneously.

When esters of general structure IV are not commercially available theycan be prepared following different synthetic pathways shown in Scheme1.

Esters of general structure IV where R2 is an alkyl group and R2′ isfluorine can be prepared from acids VI, which are converted tocorresponding esters IX and finally fluorinated in presence of a strongbase and an electrophilic source of fluorine as reported by Tengeiji etal. Molecules 2012, 17, 7356-7378.

Esters IV can be prepared from heteroaryl bromides of structure X whichare transformed into intermediates XI via palladium catalyzed reactionwith malonitrile for example see Xiang Wang et al. J. Org. Chem., 2008,73, 1643-1645. Derivatives XI can be alkylated to give esters IV whereR2′ is cyano group.

Ester IV can be prepared directly from alkylation of heteroaryl aceticesters of general structure XII.

When esters XII are not commercially available, they can be synthesisedwith three different approaches: by alcoholysis of heteroarylacetonitriles of general structure VII, via Negishi-Reformatsky couplingbetween heteroaryl bromides of structure X and tert-butyl ester ofbromoacetic acid as described by Hartwig, J. F. et al. JACS, 2003, 125,11176-11177 or by carboxylation of methyl group of compounds of generalstructure XIII in presence of a strong base as LDA (see WO9815278).

Esters of general structure IV can be prepared from N-alkylation ofnitrogen bearing heterocycles XIV (pyrazoles, pyrroles, indoles) withester of α-bromoalkanoic acid of general structure XV.

An alternative approach for the synthesis of compounds of generalstructure I, depicted in Scheme 1, consists of coupling betweenappropriate amine of general structure III with α-bromoacid of generalstructure XVI using a suitable coupling agent to give intermediate ofgeneral structure XVII. N-alkylation of nitrogen bearing heterocyclesXIV (pyrazoles, pyrroles, and indoles) with intermediates XVII offercompounds of general structure I.

Compounds of general structure I can be further modified intoderivatives Ia when R₃ contains groups that can be modified in fewsynthetic steps. For example, when R₃ contains methoxy group, it can bedemethylated and O-alkylated with different alkyl groups; or in presenceof primary amino group, this one can be alkylated to the correspondingtertiary amine or can be acylated with the appropriate carboxylic acid.

Scheme 2 describes the synthetic approach to prepare compounds ofgeneral structure Ib, where R3 is 1,2,4-oxadiazole substituted inposition 3 with an aryl or heteroaryl group. Condensation betweendiethyl alkyl malonate XVIII and amidoxime XIX gives oxadiazole XX,which can be hydrolyzed to corresponding acid XXI and coupled with theappropriate amine of general structure III using a suitable couplingagent to give compounds of general structure Ib.

In Scheme 4 it is depicted the synthesis for a single point modificationof intermediates of general structure IV, where methoxy group isreplaced by difluoromethoxy moiety. Methoxypyridine esters of generalstructure IV are converted into the corresponding pyridones XXIIfollowed by difluoromethylation of the oxygen (Makoto et al. OrganicLetters, 2006, 8, 3805-3808) to give esters of general structure IVa.Direct coupling with the appropriate amines of general structure IIIaffords final compounds I.

Scheme 4 depicts possible approaches for the synthesis of compounds ofgeneral structure I, where R3 is a bis-heteroaryl system. Thesesyntheses can be applied on intermediates of general structure XII, Vand VII containing a halogen in the R3 system. Intermediates of generalstructure II, IV, VIII can be obtained respectively from compounds V,XII and VII as described in Scheme 1. Suzuki coupling on II, IV and VIIIgives compounds of general structure IIb, IVb and VIIIb. IntermediateIVb and VIIIb can be hydrolyzed to give compounds of general structureIIb which are converted into compounds I reacting with the appropriateamines of general structure III, using a suitable coupling agent.

Enantiomers or enantiomerically enriched compositions could also beobtained by using optically active starting materials or by enantiomericresolution strategies.

Enantiomeric resolution strategies of compounds of general structure Iare reported in scheme 5. Racemic mixtures of compounds I can beseparated by chiral preparative HPLC.

Alternatively, acid of general structure II can be coupled with chiralauxiliaries such oxazolidinones to give diastereoisomers XXIIIa andXXIIIb. The resulting diastereoisomers could be separated and hydrolyzedto give the two acids in pure enantiomeric form that could be coupledwith the appropriate amine of general structure III, using a suitablecoupling agent to give compounds of general structure I as enantiomers.Alternatively racemic acids of general structure II can be solved beforeamide coupling with conventional approaches such as crystallization inpresence of a chiral amine, enzymatic resolution, chiral preparativeHPLC.

Enantiomers or enantiomerically enriched compositions could also beobtained by using optically active starting materials.

Biological Evaluation

In Vitro Cellular Assay for Activity Against S1P

CHO-S1P3 R1 cells were generated by stably transfecting wt CHO-K1 cellswith pcDNA6.2/cLumioDEST-hS1P3 and were maintained under antibioticselection with 6 μg/ml blasticidin. CHO-S1P1 MG12 cells were alsogenerated by stable transfection of wt CHO-K1 cells and were selectedwith 1 mg/ml hygromycin.

The compounds were tested on CHO-S1P3 R1 cells for their ability to actas antagonists of the sphyngosine induced intracellular Ca-flux, thatwas measured by the fluorescent calcium indicator Fluo-4 AM on aMolecular Devices FLIPR3 instrument.

Cells were seeded as 30K cells per well in a 96-well plate (black, clearbottom, TC coated) in 100 μl culture medium. After 24 h incubation cellswere loaded with 100 μL HBSS containing 20 mM HEPES buffer, 5 mMprobenecid, 4 μM FLUO-4 AM and pluronic acid 0.02% and kept at 37° C.,5% CO2 for 30 minutes. Loading solution was then washed out with HBSS-20mM Hepes buffer.

Compounds were dispensed to the cells as first addition, at the finalconcentration of 10 μM for primary screening and in 8 pointsconcentration response (30 μM-0.001 μM) with a final DMSO concentrationof 0.3%. Sphingosine was added as second addition at the finalconcentration equal to the EC80. Calcium responses were read on afluorescence imaging plate reader (FLIPR3; Molecular Devices) byexciting the cells with an argon ion laser at 488 nm. Emission wasrecorded by using a band spectrum filter (510-570 nm; emission peak ofFluo-4/Ca2+=516 nm).

The compound activity was also evaluated for the activity on Gαi pathwayboth against S1P1 receptor and S1P3 receptor.

Changes in intracellular cAMP concentrations were measured with a HTRF®assay (cAMP Dynamic 2 Kit, Cisbio Bioassays, Codolet, France), accordingto the manufacturer's protocol.

CHO-S1P1 MG12 or CHO-S1P3 R1 ready-to-use frozen cells were thawed,resuspended in DPBS (Lonza, Basel, Switzerland) with 1 mM IBMX anddispensed in 384-well low volume microplates (Greiner Bio-One GmbH,Frickenhausen, Germany) as 10000 cells in 5 μl per well. Cell treatmentwas performed in assay buffer containing PBS 0.2% BSA. The cells werepre-incubated for 15 min at room temperature with 2.5 μl of a 4-foldconcentrated compound solution either at single concentration or in aconcentration response titration (0.6% final DMSO concentration).Subsequently, 2.5 μl of a Sphingosine/forskolin solution at 4-fold therespective EC80 concentrations were added to each well except forpositive control wells, where only forskolin was added. After 45 min, 5μl of the HTRF® detection reagents (anti cAMP-Cryptate and cAMP-d2) wereadded to the cells according to the kit instructions. After 1 hourincubation at room temperature, the time resolved fluorescence was readwith an AnalystGT microplate reader (Molecular Devices, Sunnyvale,Calif., USA) with excitation at 337 nm, emission at 665 nm and 620 nm(for acceptor and donor signals, respectively).

In Vitro Phenotypic Assay: S1P Proliferation Assay in Primary CorticalAstrocytes

Primary cortical astrocytes were prepared from E17 embryos(Sprague-Dawley) rat neocortex by enzymatic dissociation. The isolatedcortices were minced into small pieces with a sterile blade, washed forthree times with dissociation medium and incubated with trypsin (0.25%)in waterbath at 37° C. for 10 mins. The pellet was placed in FBS(10%)-containing MEM medium and pipetted for 20 strokes; the cellsuspension was centrifuged at 1050 rpm for 10 mins at r.t. and thepellet was resuspended in growth medium (BME, 10% FBS, 2 mM glutamine, 1mM pyruvate, Penicillin/Streptomycin 1000 U/ml). The cells were seededin poly-D-lysine (70K-150K kD) pre-coated 75 cm² flasks on at, at 37°C., 5% CO₂ and 95% humidity. The mature cultures were grown untilastrocytes had reached confluence (12-15 days). Then, cultures areplaced in an orbital shaker and shacked (200 RPM) overnight at 37° C.,5% CO₂ and 95% humidity. Medium was then removed and the cell layercontaining mostly astrocytes was removed by trypsinization (0.25%) for15 mins at 37° C. Furthermore, after blocking trypsin with MEM 10% FBS,medium was eliminated by centrifugation at 1200 RPM. Cells are seededinto black wall, clear bottom 96-well plates (30K cells/well) in 10%FBS/BME (day 1). 24 h later, on day 2, the medium was replaced withserum free BME. On day 3, the cells were treated with the antagonistsfor 1 hr before S1P addition (S1P final concentration: 1 μM). The finalDMSO concentration was 0.1% v/v. On day 5 (48 h S1P stimulation), cellswere fixed in 4% paraformaldehyde/4% sucrose, permeabilized in 0.2%Triton-X 100, and blocked in 0.1% BSA. The primary antibody Rb-anti-Ki67(1:500, Abcam) was incubated for 3 hr at room temperature, followed bythe Alexa Fluor 546 conjugated secondary antibody. The plates wereacquired with BD Pathway 435 and the nuclear intensity of the Ki67staining measured with BD Attovision software. The proliferation wasexpressed as percentage of Ki67-positive nuclei per total nuclei.

Neurodegeneration, Neuroinflammation and Behavioural In Vivo Assays

The efficacy of the compounds of the invention on neurodegeneration andneuroinflammation can be evaluated with two different methodologicalapproaches aimed to reproduce some pathological features of Alzheimer'sdisease:

-   1) the excitotoxic insult (quisqualic acid—QUIS) in the Nucleus    Basalis Magnocellularis (NBM), characterized by severe    neurodegeneration of cholinergic neurons along with significant    neuroinflammation.-   2) the β-amyloid peptide 25-35 (Aβ25-35) injection in NBM of rats,    inducing a significant glia reaction around Aβ25-35 deposits with    modest toxicity on cholinergic neurons.    -   Readouts are based on immunochemical analysis and are: count of        cholinergic neurons (ChAT-positive), astrocytes (GFAP-positive)        and microglia (OX-42 or Iba-1 positive). The analysis is        performed by two different approaches, the visual scoring        (blind) and the digital platform APERIO®.

QUIS-treated animals can also undergo the Object Recognition Test (ORT,measuring episodic memory) or other behavioural tests to measure theimprovement of cognitive functions upon treatment with a compound of theinvention.

Animals

Three-month old male Wistar rats (Harlan, Milan, Italy) weighing 230-250g were used. The rats were housed in macrolon cages with ad lib food andwater and maintained on a 12 h light/dark cycle at 23° C. roomtemperature (RT). All experiments were carried out according to theguidelines of the European Community's Council for Animal Experiments(86/609/EEC). Efforts were made to minimize the number of animals usedand their suffering.

Quisqualic Acid and ABeta (25-35) Peptide Injections into the NucleusBasalis and Drug Treatment

The quisqualic acid (Sigma Chemical Co., Milan, Italy; dissolved inphosphate buffer at the concentration of 0.12 M volume 0.5 μl) or 10 ugof ABeta(25-35) peptide (Bachem) dissolved PBS at the concentration of10 μg/μl and aggregate at 37° for 2 h before injection volume 1 μl) wasinjected by means of an Hamilton microsyringe into the right NBM underchloral hydrate anaesthesia at the following stereotaxic coordinates:AP=−0.2, L=−2.8 from bregma and H=7 from the dura (Paxinos and Watson,1982, Casamenti et al., 1998). Controlateral NBM were injected with PBSsolution. The study was performed for 7 days after surgery. Rats wereorally (ip) administered with a compound of the invention or vehicleswith two administration, 24 h and 1 h before surgery and once daily for7 days after lesioning. Last administration was performed 1 h beforesacrifice.

Object Recognition Test

Object recognition was evaluated according to Ennanceur and Delacour(1988) and Scali et al., (1997). Briefly, the rats were placed in a greypolyvinylchloride arena (60×60×40 h cm) illuminated by a 50 W lampsuspended 50 cm above the arena. The objects to be discriminated wereprisms, pyramids and cylinders made of plastic. The day before testing,rats were allowed to explore the arena for 2 min. On the day of thetest, in the scopolamine protocol, a session of 2 trials separated by aninteratrial interval of 240 min was carried out. In the first trial(acquisition trial, Ti) two identical objects were presented in twoopposite corners of the arena. The rats were left in the arena untilcriterion of 20 s of total exploration of the objects was reached.Exploration was defined as directing the nose at a distance <2 cm to theobject and/or touching it with the nose. During the second trial(retention trial, T2) one of the objects presented in T1 was replaced bya new (differently shaped) object and the rats were left in the arenafor 5 min. The times spent exploring the familiar (F) and the new object(N) were recorded separately and the difference between the twoexploration times was taken. From one rat to the next, care was taken toavoid object and place preference by randomly changing the role of theobjects (familiar or new object) and their position in the two oppositecorners of the box during T2. Furthermore, in order to avoid olfactorystimuli the objects to be discriminated were cleaned carefully. In thetime delay procedure, T2 was performed 24 h after T1 when a spontaneousdecay of memory was presents in control rats. Drug's administrationswere performed 30 min before the acquisition trial Ti.

Immunohistochemistry

Under deep chloral hydrate anaesthesia, the rats were perfusedtranscardially with ice-cold paraformaldehyde solution (4% inphosphate-buffer, pH 7.4). The brains were postfixed for 4 h andcryoprotected in 18% sucrose solution for at least 48 h. Brains were cutin a cryostat throughout the injected area into 30 μm-thick coronalsections and placed in anti-freezer solution (phosphate-buffered salinecontaining 30% ethylene glycol and 30% glycerol) and stored at −20° C.until used for immunohistochemistry, according to the followingschedule.

Day 1 ChAT (marker of cholinergic neurons, goat antiserum, Millipore,1:200), was used as neurodegeneration marker and GFAP (marker ofastrocytes, rabbit polyclonal antibody DAKO, 1:1000) and Iba-1 (markerof microglia, rabbit antibody, Wako, 1 1:500) or OX-42 (CD11b/c, markerof activated microglia, mouse antibody, BD Biosciences Pharmingen,1:400) as neuroinflammation markers of astrocytes and microglia,respectively.

Secondary antibodies: biotinylated IgG (Vector Laboratories, Burlingame,Calif.), diluted 1:1000.

Immunohistochemical Procedure

Slices were processed as free-floating sections, briefly, the primaryantibody was added at the appropriate dilution (in Blocking buffer: PBSTwith 0.5% BSA) and left overnight under mild agitation at roomtemperature. Then the corresponding biotinylated secondary antibody (inBlocking buffer: PBST with 0.1% BSA) was added to the slices and left 90min at room temperature, under mild agitation, and then removed andwashed with PBS. Bound antibody was visualized by using Vectastain ABCKit (Vector Laboratories, Burlingame, Calif.) with DAB (VectorLaboratories, Burlingame, Calif.) as chromogen. The sections weremounted, counterstained with Ematossilin (Carlo Erba Reagents, Italy),dehydrated and coverslipped with mounting medium (Leica).

Immunohistochemical Marker Quantification

All immunohistochemical markers were quantified in the NMB area by theAperio® digital pathology platform; briefly, 4-6 slides per animal weredigitalized by using the scanner Scanscope CS (Aperio®), then the rightand left NMB areas were manually identified for each slide creating aRegion Of Interest (ROI) where specific macros of analysis were appliedto quantify the signal. Each right striatum (injected withAAV9-Ex1-AcGFP-Q138) was compared with its contralateral (left) one(injected with AAV9-Ex1-AcGFP-Q17). Data from each slide were averagedon a per animal basis and the resulting values were used for statisticalanalysis.

ChAT was quantified as number of cells per area, as a single cellpopulation. GFAP and Iba-1, were evaluated as positive pixel counts perarea in the Region of Interest (ROI).

Formulation and Administration

Compounds under formula (A) are formulated preferably in admixture witha pharmaceutically acceptable carrier, excipient or the like. Ingeneral, it is preferable to administer the pharmaceutical compositionin orally-administrable form, but certain formulations may beadministered via a parenteral, intravenous, intramuscular, transdermal,buccal, subcutaneous, suppository, nasal or other route. One of ordinaryskill in the art may modify the formulations within the teachings of thespecification to provide numerous formulations for a particular route ofadministration without rendering the compositions of the presentinvention unstable or compromising their therapeutic activity.

In particular, the modification of the present compounds to render themmore soluble in water or other vehicle, for example, may be easilyaccomplished by minor modifications (salt formulation, esterification,etc.) which are well within the ordinary skill in the art. It is alsowell within the routineer's skill to modify the route of administrationand dosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

In certain pharmaceutical dosage forms, the pro-drug form of thecompounds, especially including ester and ether derivatives, as well asvarious salt forms of the present compounds, are preferred.

One of ordinary skill in the art will recognize how to readily modifythe present compounds to pro-drug forms to facilitate delivery of activecompounds to a targeted site within the host organism or patient.

The routineer also will take advantage of favourable pharmacokineticparameters of the pro-drug forms, where applicable, in delivering thepresent compounds to a targeted site within the host organism or patientto maximize the intended effect of the compound.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975.

The composition or formulation to be administered will, in any event,contain a quantity of the active compound in an amount effective toalleviate the symptoms of the subject being treated.

While human dosage levels have yet to be optimized for the compounds ofthe invention, generally, a daily dose is from about 0.05 mg/kg to about100 mg/kg of body weight.

The amount of active compound administered will, of course, be dependenton the subject and disease state being treated, the severity of theaffliction, the manner and schedule of administration and the judgmentof the prescribing physician.

For purposes of the present invention, a prophylactically or preventiveeffective amount of the compositions according to the present invention(i.e., an amount which substantially reduces the risk that a patientwill either succumb to a disease state or condition or that the diseasestate or condition will worsen) falls within the same concentrationrange as set forth above for therapeutically effective amounts and isusually the same as a therapeutically effective amount.

In some embodiments of the present invention, one or more compounds offormula (A) are administered in combination with one or more otherpharmaceutically active agents. The phrase “in combination”, as usedherein, refers to agents that are simultaneously administered to asubject. It will be appreciated that two or more agents are consideredto be administered “in combination” whenever a subject is simultaneouslyexposed to both (or more) of the agents.

Each of the two or more agents may be administered according to adifferent schedule; it is not required that individual doses ofdifferent agents be administered at the same time, or in the samecomposition. Rather, so long as both (or more) agents remain in thesubject's body, they are considered to be administered “in combination”.

EXAMPLES Experimental Section

All reagents and solvents were obtained commercially. Air and moisturesensitive liquid solutions were transferred via syringe. The course ofreactions was followed by thin-layer chromatography (TLC) and/or liquidchromatography-mass spectrometry (HPLC-MS or UPLC-Ms). TLC analyses wereperformed on silica (Merck 60 F254) and spots revealed by UVvisualisation at 254 nm and KMnO⁴ or ninhydrin stain.

Purifications by column chromatography were performed using silicacartridges Isolute flash Si or silica (Merck 60) or with flashchromatography purification instruments (Biotage). Compounds puritieswere above 90%.

All nuclear magnetic resonance spectra were recorded using a BrukerAvance AV 400 System (400.13 MHz for ¹H) equipped with BBI a probe.

Abbreviation

THF: Tetrahydrofuran

NH₄C₁: Ammonium chloride

AcOEt: Ethyl Acetate

Na₂SO₄: Sodium sulphate

HCl: Hydrochloric acid

DMF: N,N-dimethylformamide

NaH: Sodium Hydride

H₂O: Water

DCM: dichloromethane

NaOH: sodium hydroxide

K₂CO₃: potassium carbonate

NaHCO₃: sodium hydrogencarbonate

MeOH: methanol

EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

DCE: 1,2-dichloroethane

DIPEA: N,N-diisopropyl-N-ethylamine

NaCl: sodium chloride

K₃PO₄: Tripotassium phosphate

Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium (0)

Qphos: 1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene

T₃P: Propylphosphonic Anhydride

EtOH: ethanol

Cs₂CO₃: Cesium carbonate

LiHMDS: lithium bis(trimethylsilyl)amide

H₂SO₄: Sulfuric acid

LDA: Lithium diisopropylamide

cHex: cyclohexane

NH₄OH: ammonium hydroxide

H₂: hydrogen

Pd/C: palladium on activated carbon

CDI: 1,1′-Carbonyldiimidazole

CH₃CN: Acetonitrile

Analytical Methods

Method c: Anaytical HPLC-MS were run using a Waters 2795 separationmodule equipped with a Waters Micromass ZQ (ES ionisation) and WatersPDA 2996, using a X-Bridge C18 3.5 μm 2.10×50 mm column. Gradient: 0.1%ammonia/water and acetonitrile with gradient 85/15 to 5/95 flow 0.8ml/min over 5/10 minutes. Temperature: 40° C. UV Detection at 215 and254 nm. ESI+ detection in the 80-1000 m/z range Method d: AnalyticalUPLC-MS were run using a Acquity Waters UPLC with equipped with a WatersSQD (ES ionization) and Waters Acquity PDA detector, using a column BEHC18 1.7 μm, 2.1×5.00. Temperature: 40° C. UV Detection at 215 and 254nm. ESI+ detection in the 80-1000 m/z range Gradient 0.1% ammoniumbicarbonate/water and acetonitrile with a gradient 95/5 to 15/85 flow:0.8 ml/min over 4 min.

Method e: Analytical UPLC-MS were run using a Acquity Waters UPLC withequipped with a Waters SQD (ES ionization) and Waters Acquity PDAdetector, using a column BEH C18 1.7 μm, 2.1×5.00. Temperature: 40° C.UV Detection at 215 and 254 nm. ESI+ detection in the 80-1000 m/z range.Gradient 0.04% formic acid/95% water/5% acetonitrile and CH3CN with agradient 95/5 to 0/100 flow: 0.8 ml/min over 4 minutes.

Method f: Analytical UPLC-MS were run using a Acquity Waters UPLC withequipped with a Waters SQD (ES ionization) and Waters Acquity PDAdetector, using a column BEH C18 1.7 μm, 2.1×5.00. Temperature: 40° C.UV Detection at 215 and 254 nm. ESI+ detection in the 80-1000 m/z range.Gradient 0.1% formic acid/water and 0.1% formic acid/CH₃CN with agradient 95/5 to 5/95 flow: 0.6 ml/min over 3 minutes.

Preparative HPLC Method

Method a: Preparative HPLC was run using a Waters 2767 system with abinary gradient Module Waters 2525 pump and coupled to a WatersMicromass ZQ 25 (ES) or Waters 2487 DAD, using a X-Bridge C18 5 μm19×150. Gradient 0.1% ammonia/water and methanol flow: 17 ml/min.

Method b: Preparative HPLC was run using a Waters 2767 system with abinary gradient Module Waters 2525 pump and coupled to a Waters MS3100SQ or Waters 2487 DAD, using a X-Bridge C18 5 μm 19×150. Gradient 0.1%formic acid/water and 0.1% formic acid/methanol flow: 17 ml/min.

General Synthetic Procedures

General Procedure A1 for Carboxylation

To a solution of N,N-diisopropylamine (2.1 eq) in anhydrous THF (0.4mL*mmol) cooled to −78° C., a solution of n-butyllithium (2.5 M inhexane, 2 eq) was added dropwise under an inert atmosphere. The mixturewas stirred at −78° C. for one hour and then the desired methylpyridine(1 eq) was added. The reaction mixture was stirred at −78° C. for onehour and a solution of diethyl carbonate (1.2 eq) in THF (0.3 mL*mmol)was added. The reaction mixture was allowed to warm up to roomtemperature and left stirring overnight. The mixture was quenched withH₂O and extracted twice with AcOEt. The organic layer was collected,washed with saturated sodium chloride solution, dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography.

General Procedure A2 for Reformatsky-Negishi Coupling

To prepare the Reformatsky reagent Zinc dust (1.2 eq) was suspended inanhydrous THF under N2 and Trimethylsilyl chloride 0.1 eq was addeddropwise and the resulting suspension was refluxed for 1 h. Thenbromoacetic acid tert-butyl ester (1.2 eq) was added dropwise and theresulting reaction mixture was refluxed for 2 h. The resultingReformatsky reagent was added to a degassed suspension of Bromo-aryl orheteroaryl compound (1 eq), Q-phos (0.05 eq) and Palladium source (0.05eq.) in anhydrous THF. The resulting reaction mixture was heated at 75°C. overnight. The reaction was worked up adding a saturated solution ofNH₄Cl and AcOEt. The aqueous layer was extracted again with AcOEt andthe resulting organic layers were combined, dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by silica gelchromatography.

General Procedure B1 for the Alkylation of Acid:

To a solution of heteroaryl-acetic acid (1 eq) in anhydrous THF cooledto −78° C., a solution of LiHMDS (1M 2.2 eq) in THF was added. Theresulting mixture was stirred at −78° C. for 1 hour. Then 1-iodoproprane(1.1 eq) was added portionwise and the reaction mixture was allowed towarm up to room temperature and left stirring overnight. The reactionmixture was quenched with H2O and extracted with AcOEt. The aqueouslayer was separated; the solution was acidified to pH3 with 6N HCl andextracted with AcOEt three times. The organic phases were collected,dried over Na₂SO₄ and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography.

General Procedure B2 for Alkylation—Cyclization

Ethyl 2-(5-bromopyridin-3-yl)acetate (1 eq) was dissolved in DMF (5mL*mmol); 18-crown-6 ether (0.05 eq) and NaH 60% dispersion in mineraloil (2.5 eq) were added and the mixture was stirred at room temperaturefor 30 minutes; dibromo alkane (1.1 eq) was added dropwise and reactionwas stirred at room temperature for 5 h. NaOH 15% solution in H₂O (1.5mL*mmol) was added and the mixture was stirred for 16 h at roomtemperature. H₂O was added and pH was adjusted to 3 with HCl 6N. Aqueoussolution was extracted with DCM; organic phases were collected, driedover Na₂SO₄, filtered and evaporated. The crude product was purified bysilica gel chromatography

General Procedure B3 for Alkylation

A solution of acid (1 eq) in dry THF (1.4 mL*mmol) was added dropwise toa solution of n-Butyllithium 1.6 M in n-hexane (2.2 eq) in THF (0.3mL*mmol) at −78° C. The reaction was stirred at −78° C. in inertatmosphere for 2 h; then a solution of haloalkane (1.1 eq) in THF (0.6mL*mmol) was added dropwise. Solution was allowed to warm up to roomtemperature and stirred for 16 h. H₂O was carefully added and mixturewas diluted with AcOEt. Aqueous phase was collected, acidified to pH=1with 6N HCl and extracted with AcOEt; organic layer was collected, driedover Na₂SO₄, filtered and evaporated under vacuum

General Procedure B4 for Fluoro Insertion

A solution of LiHMDS1M in THF (1.1 eq) was diluted with THF (4.0mL*mmol) and cooled to −78° C.; a solution of ethyl ester (1.0 eq) inthe same solvent (2.0 mL*mmol) was added drop-wise. The mixture wasstirred at 0° C. for 30 minutes and then cooled to −78° C. again. Asolution in THF (4.0 mL*mmol) of N-fluorobenzene sulfonimide (1.3 eq)was added dropwise; the mixture was then warmed to room temperature andstirred for 12 hours. The reaction was quenched with NH₄Cl saturatedaqueous solution, extracted with AcOEt and washed with H₂O. The organiclayer was collected and the solvent was removed under reduce pressure.The crude product was purified by silica gel chromatography.

General Procedure B5 for Alkylation of Acid and Ester

Heteroaryl acetic acid ethyl ester (1 eq) was dissolved in DMF (2mL*mmol), cesium carbonate (1.2 eq) and iodoalkane (1.1 eq) were addedand the mixture was stirred at room temperature overnight. H₂O was addedand crude extracted three times with AcOEt. Organic phases werecombined, dried over Na₂SO₄ and concentrated in vacuo. The crude productwas purified by silica gel chromatography.

General Procedure C1 for Phenol Alkylation

To a suspension of the desired phenol (1 eq) and K₂CO₃ (2 eq) in DMF,the desired alkyl bromide (4 eq) was added and the mixture was heated at70° C. for 18 hours. H2O was added and the mixture was extracted withAcOEt. The organic phase was collected and concentrated under reducedpressure. The crude product was purified by silica gel chromatography.

General Procedure D1 for Acid Hydrolysis

A solution of the desired ester in concentrated HCl (0.37 mmol/mL) wasstirred at 100° C. for two hours. The mixture was concentrated underreduce pressure and the crude product was used in the next step withoutfurther purification.

General Procedure D2 for Acid Hydrolysis

To a solution of tert-butyl ester (1 eq) in DCM (10 mL*mmol),trifluoroacetic acid (1 mL*mmol) was added and the mixture was stirredat room temperature for three days. The mixture was concentrated underreduced pressure, then was diluted with DCM and extracted with NaHCO₃saturated solution. The aqueous layer was separated, acidified to pH3with HCl 1N and extracted with DCM. The organic phase was separated,dried over Na₂SO₄ and concentrated under reduced pressure, affording thetitle compound.

General Procedure D3 for Basic Hydrolysis

To a solution of ester (1 eq) in MeOH (7.5 mL*mmol), a solution of 2NNaOH (7.5 mL*mmol) was added and the mixture was stirred at roomtemperature for 3 hours. The solvent was removed under reduced pressure,the residue was suspended in H₂O and the mixture was acidified with 1NHCl to pH3. The aqueous phase was extracted with DCM and the organiclayer was collected and dried over Na₂SO₄. The title compound wasobtained without further purification.

General Procedure E1 for the Amide Coupling with Thionyl Chloride:

To a solution of carboxylic acid (1 eq) in 1,2-dichloroethane (4.3mL*mmol) thionyl chloride (1.2 eq) and catalytic amount of DMF wereadded and the mixture was stirred at 60° C. for 4 hours. Then themixture was allowed to cool down to room temperature and the desiredamine (1.2 eq) and DIPEA (3 eq) were added. The mixture was stirred atroom temperature overnight then washed with saturated NaHCO₃ solution,the organic layer collected and the solvent was removed under reducepressure. The crude product was purified by silica gel chromatography.

General procedure E2 for amide coupling with EDC and1-hydroxybenzotriazole hydrate

To a solution of acid (1 eq) in DMF (3 mL*mmol), amine (1.1 eq),1-hydroxybenzotriazole hydrate (0.36 eq) and EDC (1.5 eq) were added.The mixture was stirred at room temperature for one hour. NaHCO₃saturated solution was added and the mixture was extracted with DCM. Thecombined organic extracts were washed with saturated NaCl solution,dried over Na₂SO₄ and evaporated. The crude product was purified bysilica gel chromatography.

General Procedure E3 for the Amide Coupling with N-BromosuccinimideTriphenylphosphine:

To a solution of triphenylphosphine (1.6 eq) in DCM (1 ml*mmol ofcarboxylic acid) cooled at 0° C., N-bromosuccinimide (1.6 eq) was addedand the mixture left at 0° C. for 30 minutes. The desire carboxylic acid(1 eq) was added and the reaction was allowed to warm up to roomtemperature and lest stirring for 45 minutes. Amine (2.5 eq) was addedand the mixture was left stirring for 18 hours at room temperature. Themixture was washed with 1N HCl solution and NaHCO₃ saturated solution.The organic phase was collected and the solvent was removed underreduced pressure. The crude product was purified by silica gelchromatography.

General Procedure E4 for the Amide Coupling with T3P

To a solution of carboxylic acid (1 eq) and amine (1 eq) in AcOEt, DIPEA(2 eq) was added and solution cooled to 0° C. T3P 50% solution in AcOEt(1.5 eq) was added and reaction was stirred for 12 h at roomtemperature. NaHCO₃ saturated solution was added, organic layer wasseparated, dried over Na₂SO₄, filtered and evaporated. The crude productwas purified by silica gel chromatography.

General Procedure F1 for Amide Coupling of Ester

To a solution of acid (1 eq 0.12 g, 0.47 mmol) in DMF (3 mL*mmol), amine(1.1 eq), 1-hydroxybenzotriazole hydrate (0.36 eq) and EDC (1.5 eq) wereadded. The mixture was stirred at room temperature for one hour. NaHCO₃saturated solution was added and the mixture was extracted with DCM. Thecombined organic extracts were washed with saturated NaCl solution,dried over Na₂SO₄ and evaporated. The crude product was purified bysilica gel chromatography.

General Procedure F1 for Nitrile Alcoholysis

To a solution of EtOH (2 mL*mmol of nitrile) H2SO₄ concentrated (0.76mL*mmol of nitrile) was added dropwise and the desired nitrile (1 eq)was added portion wise. The solution was stirred at 100° C. for threehours. The mixture was added dropwise to a solution of NaHCO₃ (3.00g*mmol of nitrile) in H₂O (7.5 mL*mmol of nitrile) and it was extractedtwice with DCM. The organic layer were collected, dried and evaporated,affording the desired compound.

General Procedure C1 for Phenol Alkylation

To a suspension of the desired phenol (1 eq) and K₂CO₃ (2 eq) in DMF,the desired alkyl bromide (4 eq) was added and the mixture was heated at70° C. for 18 hours. H₂O was added and the mixture was extracted withAcOEt. The organic phase was collected and concentrated under reducedpressure. The crude product was purified by silica gel chromatography.

General Procedure J1 for Alkylation

To a solution of N-heterocycle (1 eq) in DMF (2 ml*mmol), NaH (60% inmineral oil, 1.2 eq) was added and the mixture was stirred at roomtemperature for 30 minutes. 2-Bromo-alkanoic acid ethyl ester (1.1 eq)was added and the reaction was left stirring at room temperatureovernight. Saturated NaCl solution was added and the mixture wasextracted with DCM. The organic phase was collected, dried over Na₂SO₄and concentrated under reduced pressure. The crude product was purifiedby silica gel chromatography.

General Procedure J2 for Alkylation

A suspension of N-heterocycle (1 eq) and K₂CO₃ (2 eq) in acetone (4mL*mmol) was heated at 55° C. for 10 minutes and then was allowed tocool down to room temperature. 2-Bromo-alkanoic acid ethyl ester (1.1eq) was the added and the mixture was heated at 55° C. for 18 hours. Thesolvent was removed under reduced pressure and the crude product wassuspended in DCM and washed with H2O. The organic phase was collected,dried over Na₂SO₄ and concentrated under reduced pressure.

General Procedure O for Suzuki Coupling

Ester/Acid (1 eq) was dissolved in degassed dioxane (4 mL*mmol), boronicacid or ester (1 eq), K₃PO₄ (1.7 eq), phosphine (0.02 eq), Pd₂(dba)₃(0.01 eq) were added then degassed H₂O (0.5 mL*mmol) was added andreaction mixture was heated at 100° C. in a pressure tube for 16 h.AcOEt and NaCl saturated solution were added. Organic phase wascollected and evaporated. The crude product was purified by silica gelchromatography.

Example 1 2-(5-Bromo-pyridin-3-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

2-(5-Bromo-pyridin-3-yl)-pentanoic acid

To a solution of (5-Bromo-pyridin-3-yl)-acetic acid (2.00 g, 9.2 mmol)in anhydrous THF (20 mL) cooled to −78° C., a solution of LiHMDS (1M, 20mmol) in THF was added. The resulting mixture was stirred at −78° C. for1 hour. Then 1-iodo-proprane (1.70 g, 10.2 mmol) was added portionwiseand the reaction mixture was allowed to warm up to room temperature andleft stirring overnight. The reaction mixture was quenched with H₂O andextracted with AcOEt. The aqueous layer was separated; the solution wasacidified to pH3 with HCl 6N and extracted with AcOEt three times. Theorganic phases were collected, dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gelchromatography (cHex/AcOEt 1/1) to afford the title compound (1.2 g,50%).

C₁₀H₁₂BrNO₂ Mass (calculated) [258.12]; (found) [M+H]⁺=269.

2-(5-Bromo-pyridin-3-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide

To a solution of 2-(5-bromo-pyridin-3-yl)-pentanoic acid (0.12 g, 0.47mmol) in DCE (2 mL) thionyl chloride (0.08 g, 0.56 mmol) and catalyticamount of DMF were added and the mixture was stirred at 60° C. for fourhours. Then the mixture was allowed to cool down to room temperature and5-bromo-pyridin-2-ylamine (0.10 g, 0.59 mmol) and DIPEA (0.18 g, 1.395mmol) were added. The mixture was stirred at room temperature overnightthen washed with sodium bicarbonate saturated solution, the organiclayer collected and the solvent was removed under reduce pressure. Thecrude product was purified by silica gel chromatography (cHex/AcOEt1/1), to afford the title compound (0.05 g, 25%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.62 (d, J=2.1 Hz, 1H), 8.49 (d, J=2.1Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.98-7.91 (m,2H), 7.81 (dd, J=8.8, 2.4 Hz, 1H), 3.47 (t, J=7.5 Hz, 1H), 2.23-2.12 (m,1H), 1.87-1.75 (m, 1H), 1.44-1.24 (m, 2H), 0.96 (t, J=7.3 Hz, 3H).

C₁₅H₁₅Br₂N₃O, Calculated [413.11]. found [M+H⁺] 414, RT=1.74 (method f).

Example 2 2-(5-Bromo-pyridin-3-yl)-hexanoic acid(5-bromo-3-fluoro-pyridin-2-yl)-amide

2-(5-Bromo-pyridin-3-yl)-hexanoic acid

The title compound was obtained following general procedure foralkylation B1 and starting from (5-bromo-pyridin-3-yl)-acetic acid and1-Iodo-butane (1.82 g, 51%).

C₁₁H₁₄BrNO₂ Mass (calculated) [272]; (found) [M+H]⁺=274.

5-Bromo-3-fluoro-pyridin-2-ylamine

To a solution of 3-fluoro-pyridin-2-ylamine (0.30 g, 2.68 mmol) inacetonitrile (15 mL), in inert atmosphere, N-bromosuccinimide (0.48 g,2.68 mmol) was added. The mixture was stirred for 4 hours. Solvent wasremoved under reduced pressure and the crude product was purified bysilica gel chromatography (cHex/AcOEt 66/34) to give the title compound(0.46 g, 89%).

C₅H₄BrFN₂ Mass (calculated) [191]; (found) [M+H]⁺=193.

2-(5-Bromo-pyridin-3-yl)-hexanoic acid(5-bromo-3-fluoro-pyridin-2-yl)-amide

The title compound was obtained following general procedure E1 for amidecoupling and starting from 2-(5-bromo-pyridin-3-yl)-hexanoic acid and5-bromo-3-fluoro-pyridin-2-ylamine, (0.10 g, 34%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.60 (d, J=2.2 Hz, 1H), 8.49 (d, J=2.2Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.97 (t, J=2.2 Hz, 1H), 7.78 (s, 1H),7.64 (dd, J=9.0, 2.0 Hz, 1H), 3.90 (bs, 1H), 2.28-2.14 (m, 1H),1.88-1.74 (m, 1H), 1.46-1.18 (m, 4H), 0.89 (t, J=7.1 Hz, 3H).C₁₆H₁₆Br₂FN₃O, Calculated [445.12]. found [M+H⁺], 2Br pattern 446,RT=1.64 (method f).

Example 3N-(5-Bromo-6-fluoro-pyridin-2-yl)-2-(5-bromo-pyridin-3-yl)-3-methyl-butyramide

2-(5-Bromo-pyridin-3-yl)-3-methyl-butyric acid

The title compound was prepared following general procedure B1 for thealkylation of acid. (1.80 g, 61%).

Mass (calculated C₁₀H₁₂BrNO₂ [258]. found [M+1]=258-260 bromine pattern.

N-(5-Bromo-6-fluoro-pyridin-2-yl)-2-(5-bromo-pyridin-3-yl)-3-methyl-butyramide

Amide coupling was performed with thionyl chloride following theprocedure E4. The crude product was purified by silica gelchromatography eluting (CHex/AcOEt 0-40%) to give title compound (0.09g, 36%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.62 (d, J=2.2 Hz, 1H), 8.46 (d, J=1.9Hz, 1H), 8.05-7.97 (m, 2H), 7.93 (t, J=8.5 Hz, 1H), 7.84 (bs, 1H), 2.98(d, J=10.2 Hz, 1H), 2.52-2.38 (m, 1H), 1.12 (d, J=6.5 Hz, 3H), 0.79 (d,J=6.6 Hz, 3H).

C15H14N3OFBr2, Calculated [431.10]. found [M+H⁺]432, RT=1.79 (method f).

Example 4 1-(5-Bromo-pyridin-3-yl)-cyclobutanecarboxylic acid(5-bromo-pyridin-2-yl)-amide

1-(5-Bromo-pyridin-3-yl)-cyclobutane carboxylic acid

Ethyl 2-(5-bromopyridin-3-yl)acetate (1.0 g, 4.09 mmol, 1 eq) wasdissolved in DMF (20 mL); 18-crown-6 ether (0.054 g, 0.205 mmol, 0.05eq) and NaH 60% dispersion in mineral oil (0.41 g, 10.2 mmol, 2.5 eq)were added and the mixture was stirred at room temperature for 30minutes; 1,3-dibromopropane (0.46 mL, 4.50 mmol, 1.1 eq) was addeddropwise and reaction was stirred at room temperature for 5 h. NaOH 15%solution in H₂O (10 mL) were added and the mixture was stirred for 16 hat room temperature. H₂O was added and pH was adjusted to pH=3 with HCl6N. Aqueous solution was extracted with DCM (2×20 mL), organic phaseswere collected, dried over Na₂SO₄, filtered and evaporated. The crudeproduct was purified by silica gel chromatography (cHex/AcOEt 5%-60%) togive the title compound (0.38 g, 37% over two steps).

C₁₀H₁₀BrNO₂ Mass (calculated) [256]. found [M+1]=256-258 brominepattern.

1-(5-Bromo-pyridin-3-yl)-cyclobutanecarboxylic acid(5-bromo-pyridin-2-yl)-amide

Amide coupling on 1-(5-bromo-pyridin-3-yl)-cyclobutane carboxylic acidand 5-bromo-pyridin-2-ylamine was performed using general procedure E2to give the title compound (0.015 g, 11%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.66-8.56 (m, 2H), 8.29-8.24 (m, 1H),8.19-8.12 (m, 1H), 7.88-7.76 (m, 2H), 7.58 (s, 1H), 3.01-2.89 (m, 2H),2.63-2.51 (m, 2H), 2.24-1.93 (m, 2H).

C₁₅H₁₃N₃OBr₂, Calculated [411.09]. found [M+H⁺], 2 Br pattern 412,RT=1.61 (method f).

Example 5 1-(5-Bromo-pyridin-3-yl)-cyclopentanecarboxylic acid(5-bromo-pyrazin-2-yl)-amide

1-(5-Bromo-pyridin-3-yl)-cyclopentanecarboxylic acid

Starting from 1-(5-bromo-pyridin-3-yl)-acetic acid ethyl ester, thetitle compound was synthesised using the general procedure B2 forcyclization, followed by basic hydrolysis (D3) (0.66 g, 59% over twosteps).

Mass (calculated) C₁₁H₁₂BrNO_(2 [270)]. found [M−1]=270-272 brominepattern.

1-(5-Bromo-pyridin-3-yl)-cyclopentanecarboxylic acid(5-bromo-pyrazin-2-yl)-amide

Amide coupling was performed with thionyl chloride following theprocedure Elto give the title compound (0.021 g, 9%).

¹H NMR (400 MHz, Chloroform-d) δ 9.31 (d, J=1.7 Hz, 1H), 8.62 (dd,J=10.7, 2.1 Hz, 2H), 8.28 (d, J=1.7 Hz, 1H), 7.86 (t, J=2.1 Hz, 1H),7.53 (s, 1H), 2.71-2.55 (m, 2H), 2.17-2.03 (m, 2H), 1.99-1.73 (m, 4H).

C₁₅H₁₄N₄OBr₂, Calculated [426.11]. found [M+H⁺], 2Br pattern, 427,RT=1.61 (method f).

Example 6 1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid(5-chloro-pyridin-2-yl)-amide

(5-Chloro-pyridin-3-yl)-acetic acid tert-butyl ester

The title compound was synthesized from 3-bromo-5-chloropyridine usinggeneral procedure A2 for alkylation (8.20 g, 77%).

C₁₁H₁₄ClNO₂ Mass (calculated) [227]. found [M+1]=228-230 chlorinepattern.

1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid tert-butyl ester

The title compound was prepared using the general procedure B2 forcyclization starting from (5-Chloro-pyridin-3-yl)-acetic acid tert-butylester and 1,3-diiodopropane (0.47 g, 37%).

C₁₄H₁₈ClNO₂ Mass (calculated) [267]. found [M+1]=268-270 chlorinepattern.

1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid

The acid was obtained from1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid tert-butyl esterusing general procedure D2 for acid hydrolysis (0.33 g, quant.).

C₁₀H₁₀ClNO₂ Mass (calculated) [211]. found [M+1]=268-270 chlorinepattern.

1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid(5-chloro-pyridin-2-yl)-amide

Starting from 1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid and5-bromo-pyridin-2-ylamine amide coupling was performed with thionylchloride following the procedure E1To give the title compound (0.05 g,4%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.56 (d, J=2.2 Hz, 1H), 8.53 (d, J=2.2Hz, 1H), 8.20 (d, J=8.9 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.70 (t, J=2.2Hz, 1H), 7.67 (dd, J=8.9, 2.4 Hz, 1H), 7.58 (s, 1H), 3.03-2.90 (m, 2H),2.64-2.51 (m, 2H), 2.25-2.09 (m, 1H), 2.09-1.94 (m, 1H).

C₁₅H₁₃N₃OCl₂, Calculated [322.19]. found [M+H⁺], 322, RT=1.53 (methodf).

Example 7 1-(6-Chloro-5-cyano-pyridin-3-yl)-cyclobutanecarboxylic acid(5-chloro-pyridin-2-yl)-amid

(6-Chloro-5-cyano-pyridin-3-yl)-acetic acid tert-butyl ester

The title compound was synthesized from 5-Bromo-2-chloronicotinonitrileusing general procedure A2 for alkylation. (1.60 g, 35%).

Mass (calculated) Cl₂H₁₃ClN₂O₂ [252]. found [M+1]=253.

1-(6-Chloro-5-cyano-pyridin-3-yl)-cyclobutanecarboxylic acid

The title compound was prepared using the general procedure B2 forcyclization, followed by acid hydrolysis using general procedure D2.(0.18 g, 30%).

Mass (calculated) C₁₁H9ClN₂O₂ [236]. found [M+1]=237.

1-(6-Chloro-5-cyano-pyridin-3-yl)-cyclobutanecarboxylic acid(5-chloro-pyridin-2-yl)-amide

Amide coupling was performed following the procedure E1, starting from1-(6-chloro-5-cyano-pyridin-3-yl)-cyclobutanecarboxylic acid and acid(5-chloro-pyridin-2-yl)-amine to give the title compound (0.066 g, 50%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.64 (d, J=2.5 Hz, 2H), 8.24-8.07 (m,2H), 8.03 (d, J=2.5 Hz, 1H), 7.76 (s, 1H), 7.69 (dd, J=9.0, 2.5 Hz, 1H),3.17-2.71 (m, 2H), 2.64-2.29 (m, 2H), 2.36-1.92 (m, 2H).

C₁₆H₁₂N₄OCl₂, Calculated [347.20]. found [M+H⁺], 347, RT=1.59 (methodf).

Example 8 2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid(5-chloro-pyrazin-2-yl)-amide

(6-Chloro-5-cyano-pyridin-3-yl)-acetic acid tert-butyl ester

The title compound was synthesized following the general procedure A2starting from 5-bromo-2-chloro-nicotinonitrile. The crude product waspurified by silica gel chromatography (cHex/AcOEt gradient) to give thetitle compound (0.85 g, 75% y).

¹H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.97 (s, 1H), 3.58 (s, 2H), 1.46(s, 9H).

2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid tert-butyl ester

Alkylation was performed following the general procedure B1 startingfrom (6-Chloro-5-cyano-pyridin-3-yl)-acetic acid tert-butyl ester, togive the title compound (0.60 g, 60% y).

C₁₅H₁₉ClN₂O₂ Mass (calculated) [294]; (found) [M+H]⁺=295.

2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid

The title compound was synthesized following the general procedure D2starting from 2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acidtert-butyl ester; (0.12 g, 98% y).

C₁₁H₁₁ClN₂O₂ Mass (calculated) [238]; (found) [M+H]⁺=239.

2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid(5-chloro-pyrazin-2-yl)-amide

The title product was synthesized following the general procedure E2starting from 2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid and5-Chloro-pyrazin-2-ylamine, (0.10 g, 53%).

¹H NMR (400 MHz, Chloroform-d3) δ 9.30 (s, 1H), 8.56 (d, J=2.3 Hz, 1H),8.27 (s, 1H), 8.18 (d, J=2.3 Hz, 1H), 7.92 (s, 1H), 3.59 (t, J=7.6 Hz,1H), 2.27-2.12 (m, 1H), 1.90-1.80 (m, 1H), 1.46-1.19 (m, 2H), 0.98 (t,J=7.3 Hz, 3H).

C₁₅H₁₃N₅OCl₂, Calculated [350.20]. found [M+H⁺], 2 C₁ pattern 350-352,RT=1.60 (method f).

Example 9 2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

(6-Chloro-5-fluoro-pyridin-3-yl)-acetic acid tert-butyl ester

The title compound was synthesized following the general procedure A2starting from 5-bromo-2-chloro-3-fluoro-pyridine. The crude product waspurified by silica gel chromatography (cHex/AcOEt gradient) to give(6-Chloro-5-fluoro-pyridin-3-yl)-acetic acid tert-butyl ester (0.36 g,30%).

C₁₁H₁₃ClFNO₂ Mass (calculated) [245]; (found) [M+H]⁺=246.

2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid tert-butyl ester

The title compound was synthesized following the general procedure B1starting from (6-Chloro-5-fluoro-pyridin-3-yl)-acetic acid tert-butylester. The crude product was purified by silica gel chromatography(cHex/AcOEt gradient) to give2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid tert-butyl ester (0.17g, 56%).

C₁₄H₁₉ClFNO₂ Mass (calculated) [287]; (found) [M+H]⁺=288.

2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid

The title compound was synthesized following the general procedure D2starting from (2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acidtert-butyl ester (0.16 g, quant.).

C₁₀H₁₁ClFNO₂ Mass (calculated) [231]; (found) [M+H]⁺=232.

2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

The title compound was synthesized following the general procedure E1starting from 2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid and5-Bromo-pyrazin-2-ylamine (0.03 g, 33%).

¹H NMR (400 MHz, Methanol-d4) δ 9.20 (d, J=1.5 Hz, 1H), 8.45 (d, J=1.5Hz, 1H), 8.23 (d, J=1.9 Hz, 1H), 7.84 (dd, J=9.4, 1.9 Hz, 1H), 3.90 (dd,J=8.3, 7.0, Hz, 1H), 2.20-2.06 (m, 1H), 1.86-1.72 (m, 1H), 1.47-1.19 (m,2H), 0.96 (t, J=7.4 Hz, 3H).

C₁₄H₁₃N₄OFC₁Br, Calculated [387.63]. found [M+H⁺], Cl—Br pattern 389,RT=1.77 (method f).

Example 10 2-(5-Bromo-pyridin-3-yl)2-Fluoro-pentanoic acid(5-bromo-pyridin-2-yl) amide

2-(5-Bromo-pyridin-3-yl)-pentanoic acid

To a solution of (5-Bromo-pyridin-3-yl) acetic acid (2.0 g, 9.3 mmol, 1eq) in anhydrous THF cooled to −78° C., a solution of LiHMDS (20.4 mL,20.4 mmol, 2.2 eq) in THF was added. The resulting mixture was stirredat −78° C. for 1 hour. Then 1-iodopropane (1.0 mL, 10.2 mmol, 1.1 eq)was added portionwise and the reaction mixture was allowed to warm up toroom temperature and left stirring overnight. The reaction mixture wasquenched with H₂O and extracted with AcOEt. The aqueous layer wasseparated; the solution was acidified to pH=3 with 6N HCl and extractedwith AcOEt. The organic phases were collected, dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography (cHex: AcOEt 92:8 to 34:66) to give the titlecompound (1.2 g, 50%).

C₁₀H₁₂BrNO₂ mass (calculated) [258]; (found) [M+H]⁺=259 m/z.

2-(5-Bromo-pyridin-3-yl)-pentanoic ethyl ester

To a solution of 2-(5-Bromo-pyridin-3-yl)-pentanoic acid (1.50 g, 5.8mmol, 1 eq) in EtOH (10 mL), H2SO₄ (0.5 mL, 2.6 eq, 15.2 mmol) was addedand the mixture was stirred at 85° C. for 12 hours. Then the mixture wasallowed to cool to room temperature. The mixture was concentrated underreduced pressure, dissolved in DCM and washed with sodium bicarbonatesaturated solution. The organic layer was collected and the solvent wasremoved under reduce pressure to give the desired product employed inthe next step without further purification (1.5 g, 88%).

C₁₂H₁₆BrNO₂ mass (calculated) [286]; (found) [M+H]⁺=287 m/z.

2-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic ethyl ester

A solution of LiHDMS (1M in THF, 0.58 mL, 1.1 eq) was diluted with THF(2.0 mL) and cooled to −78° C.; a solution of the2-(5-Bromo-pyridin-3-yl)-pentanoic ethyl ester (0.15 g, 0.52 mmol, 1.0eq) in the same solvent (1.0 mL) was added dropwise. The mixture wasstirred at 0° C. for 30 minutes and then cooled to −78° C. again. Asolution in THF (2.0 mL) of N-fluorobenzene sulfonimide (0.22 g, 0.68mmol, 1.3 eq) was added dropwise; the mixture was then warmed to roomtemperature and stirred for 12 hours. The reaction was quenched withNH₄Cl saturated aqueous solution, extracted with AcOEt and washed withH₂O. The organic layer was collected and the solvent was removed underreduce pressure. The crude product was purified by silica gelchromatography (cHex: AcOEt 100:0 to 80:20) give the desired product asan orange oil (0.10 g, 63%).

C₁₂H₁₅BrFNO₂ mass (calculated) [304]; (found) [M+H]⁺=305 m/z.

2-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic carboxylic acid

To a solution of 2-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic ethyl ester(0.48 g, 1.6 mmol, 1 eq) in MeOH (3 mL), a solution of 2N NaOH (3 mL, 6mmol, 4 eq) was added and the mixture was stirred at room temperaturefor 3 hours. The solvent was removed under reduced pressure, the residuewas suspended in H₂O and the mixture was acidified with 1N HCl to pH=3.The aqueous phase was extracted with DCM and the organic layer wascollected and dried over Na₂SO₄. The title compound was isolated withoutfurther purification (0.41 g, 95%).

C₁₀H₁₁BrFNO₂ Mass (calculated) [276]; (found) [M+H]⁺=277 m/z.

2-(5-Bromo-pyridin-3-yl)2-Fluoro-pentanoic acid(5-bromo-pyridin-2-yl)-amide

To a solution of 2-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic carboxylicacid (0.12 g, 0.44 mmol, 1 eq) in DMF (1.5 mL), 5-Bromo-2-aminopyridine(0.08 g, 0.48 mmol, 1.1 eq), 1-hydroxybenzotriazole hydrate (0.02 g,0.13 mmol, 0.3 eq) and EDC (0.10 g, 0.52 mmol, 1.2 eq) were added. Themixture was stirred at room temperature for one hour. NaHCO₃ saturatedsolution was added and the mixture was extracted with DCM. The combinedorganic extracts were washed with saturated NaCl solution, dried overNa₂SO₄ and evaporated. The crude product was purified by silica gelchromatography (cHex: AcOEt 100:0 to 77:23) to give the title compound(0.07 g, 38%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.76-8.68 (m, 2H), 8.61 (d, J=2.3 Hz,1H), 8.29 (d, J=2.4 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.01 (t, J=2.3 Hz,1H), 7.76 (dd, J=8.8, 2.4 Hz, 1H), 2.42-2.21 (m, 1H), 2.18-1.99 (m, 1H),1.47-1.31 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).

C₁₅H₁₄Br₂FN₃O, Calculated [431.10]. found [M+H⁺], 432, RT=2.35 (methode).

Example 11 2-(5-Bromo-pyridin-3-yl)-2-methyl-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

2-(5-Bromo-pyridin-3-yl)-propionic acid

(5-Bromo-pyridin-3-yl)-acetic acid was alkylated with iodomethane usinggeneral procedure B1 for the alkylation of acid to give the titleproduct (0.6 g, 61%).

C₈H8BrNO₂ Mass (calculated) [230]. found [M+1]=230-232 bromine pattern.

2-(5-Bromo-pyridin-3-yl)-2-methyl-pentanoic acid

2-(5-Bromo-pyridin-3-yl)-propionic acid was alkylated using generalprocedure B1 for the alkylation, heating at 50° C. to give the titlecompound (0.1 g, 28%). C₁₁H₁₄BrNO₂ Mass (calculated) [272]. found[M+1]=272-274 bromine pattern.

2-(5-Bromo-pyridin-3-yl)-2-methyl-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

Amide coupling was performed with thionyl chloride following theprocedure E1, starting from 2-(5-bromo-pyridin-3-yl)-2-methyl-pentanoicacid and 5-bromo-pyrazin-2-yl)-amine to give the title compound afterpreparative HPLC in basic condition (0.02 g, 10%).

¹H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.10 (d, J=2.1 Hz, 1H),8.61-8.53 (m, 2H), 8.44 (d, J=2.1 Hz, 1H), 7.91 (t, J=2.1 Hz, 1H),2.16-2.03 (m, 1H), 2.01-1.83 (m, 1H), 1.57 (s, 3H), 1.20-1.02 (m, 2H),0.85 (t, J=7.1 Hz, 3H).

C₁₅H₁₆N₄OBr₂, Calculated [428.1]. found [M+H⁺], 2Br pattern 429, RT=1.66(method f).

Example 12 2-(6-Bromo-pyridin-2-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

(6-Bromo-pyridin-2-yl)-acetic acid ethyl ester

To a solution of N,N-diisopropylamine (1.85 g, 18.31 mmol) in anhydrousTHF (7 mL) cooled to −78° C., a solution of n-butyllithium (2.5 M inhexane, 17.44 mmol) was added drop wise under inert atmosphere. Themixture was stirred at −78° C. for one hour and then2-bromo-6-methylpyridine (1.5 g, 8.7 mmol). The reaction mixture wasstirred at −78° C. for one hour and a solution of diethyl carbonate(1.23 g, 10.46 mmol) in THF (3 mL) was added. The reaction mixture wasallowed to warm up to room temperature and left stirring overnight. Themixture was quenched with H₂O and extracted twice with AcOEt. Theorganic layer was collected, washed with saturated sodium chloridesolution, dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude was purified by chromatography on silica gel (cHex/AcOEt 70/30) togive the title compound as an yellow oil (1.16 g, 55%).

C₉H₁₀BrNO₂ Mass (calculated) [244]; (found) [M+H]⁺=246.

2-(6-Bromo-pyridin-2-yl)-pentanoic acid ethyl ester

The title compound was obtained following the general procedure B1 andstarting from (6-bromo-pyridin-2-yl)-acetic acid ethyl ester (0.85 g,63%).

Cl₂H16BrNO₂ Mass (calculated) [286]; (found) [M+H]⁺=288.

2-(6-Bromo-pyridin-2-yl)-pentanoic acid

To a solution of 2-(6-bromo-pyridin-2-yl)-pentanoic acid ethyl ester(0.40 g, 1.4 mmol) in MeOH (3 mL), a solution of 2N NaOH (3 ml) wasadded and the mixture was stirred at room temperature for 3 hours. Thesolvent was removed under reduced pressure, the crude product wassuspended in H₂O and the mixture was acidified with 1N HCl to pH3. Theaqueous phase was extracted with DCM and the organic layer was collectedand dried over Na₂SO₄. The title compound was obtained in quantitativeyield without further purification.

C₁₀H₁₂BrNO₂ Mass (calculated) [258]; (found) [M+H]⁺=260.

2-(6-Bromo-pyridin-2-yl)-pentanoic acid (5-bromo-pyrazin-2-yl)-amide

To a solution of 2-(2-bromo-pyridin-4-yl)-pentanoic acid (0.12 g, 0.47mmol) in DMF (1.5 mL), 5-bromo-pyrazin-2-ylamine (0.09 g, 0.51 mmol),1-hydroxybenzotriazole hydrate (0.02 g, 0.17 mmol) and EDC (0.13 g, 0.70mmol) were added. The mixture was stirred at room temperature for onehour. NaHCO₃ saturated solution was added and the mixture was extractedwith DCM. The combined organic extracts were washed with saturated NaClsolution, dried over Na₂SO₄ and evaporated. The crude product waspurified by silica gel chromatography (cHex/AcOEt 75/25) to give thetitle compound (0.02 g, 8%).

¹H NMR (400 MHz, Chloroform-d3) δ 9.59 (s, 1H), 9.29 (d, J=1.4 Hz, 1H),8.37 (d, J=1.4 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H),7.27 (d, J=7.7 Hz, 1H), 3.75 (t, J=7.7 Hz, 1H), 2.21-2.16 (m, 1H),2.08-1.92 (m, 1H), 1.45-1.21 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).

C₁₅H₁₅Br₂N₃O, Calculated [414.09]. found [M+H⁺] 415, RT=1.71 (method f).

Example 13 2-(2-Bromo-pyridin-4-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

(2-Bromo-pyridin-4-yl)-acetic acid tert-butyl ester

To a solution of diisopropylamine (2.1 g, 20.93 mmol) in anhydrous THF(30 mL) under nitrogen, cooled at −78° C., a solution of n-butyllithiumin hexane (2.5 M, 19.18 mmol) was added dropwise. The mixture wasallowed to warm up to −30° C. and left stirring for 30 minutes. Then thereaction was cooled again to −78° C. and a solution of2-bromo-4-methylpyridine (3.0 g, 17.44 mmol) in THF (10 mL) was added.The reaction turned to dark orange and it was stirred at −30° C. for 30minutes. Then the reaction was cooled to −78° C. and a solution ofdi-tert-butyl dicarbonate (0.18 g, 19.18 mmol) in THF (10 ml) was added.Then the reaction mixture was allowed to warm up to room temperature andlet stirring overnight. The mixture was quenched with H₂O and extractedwith AcOEt twice. The organic layer was separated, washed with NaClsaturate solution, dried over Na₂SO₄ and concentrated under reducedpressure. The crude was purified by silica gel chromatography(cHex/AcOEt 80/20) to give the title compound (0.81 g, 13%).

C₁₁H₁₄BrNO₂ Mass (calculated) [272]; (found) [M+H]⁺=274.

2-(2-Bromo-pyridin-4-yl)-pentanoic acid tert-butyl ester

The title compound was obtained following general procedure foralkylation B1 and starting from (2-bromo-pyridin-4-yl)-acetic acidtert-butyl ester (0.83 g, 3.05 mmol), (0.68 g, 71%).

C₁₄H₂0BrNO₂ Mass (calculated) [314]; (found) [M+H]⁺=316.

2-(2-Bromo-pyridin-4-yl)-pentanoic acid

To a solution of 2-(2-Bromo-pyridin-4-yl)-pentanoic acid tert-butylester (0.68 g, 2.16 mmol) in DCM (20 mL), trifluoroacetic acid (2 mL)was added and the mixture was stirred at room temperature for threedays. The mixture was concentrated under reduced pressure, then wasdiluted with DCM and extracted with NaHCO₃ saturated solution. Theaqueous layer was separated, acidified to pH3 with HCl 1N and extractedwith DCM. The organic phase was separated, dried over Na₂SO₄ andconcentrated under reduced pressure, affording the title compound (0.44g, 72%).

C₁₀H₁₂BrNO₂ Mass (calculated) [258]; (found) [M+H]⁺=260.

2-(2-Bromo-pyridin-4-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide

The title compound was obtained following the general procedure E2 forcoupling with EDC and starting from 2-(2-bromo-pyridin-4-yl)-pentanoicacid and 5-bromo-pyridin-2-ylamine (0.05 g, 30%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.34 (d, J=5.1 Hz, 1H), 8.31 (d, J=2.5Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.89 (s, 1H), 7.81 (dd, J=8.8, 2.5 Hz,1H), 7.52 (s, 1H), 7.28 (m, 1H), 3.42 (t, J=7.5 Hz, 1H), 2.23-2.09 (m,1H), 1.88-1.74 (m, 1H), 1.34 (m, 2H), 0.96 (t, J=7.3 Hz, 3H).

C₁₅H₁₅Br₂N₃O, Calculated [413.11]. found [M+H+] 414, RT=1.75 (method f).

Example 14 2-(2-Methoxy-pyridin-4-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

2-(Methoxy-pyridin-4-yl)-acetic acid ethyl ester

The title compound was synthesized following the general procedure A1starting from 2-methoxy-4-methyl-pyridine. (4.63 g, 73%)

C₁₀H₁₃NO₃ Mass (calculated) [195]; (found) [M+H]⁺=196.

2-(2-Methoxy-pyridin-4-yl)-pentanoic acid ethyl ester

The title compound was synthesized following the general procedure B1starting 2-methoxy-pyridin-4-yl)-acetic acid ethyl ester. Title compoundwas obtained in (0.75 g, 75%).

C₁₃H₁₉NO₃ Mass (calculated) [237]; (found) [M+H]⁺=238.

2-(2-Methoxy-pyridin-4-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide

To 2-(2-Methoxy-pyridin-4-yl)-pentanoic acid ethyl ester (0.150 g, 0.6mmol, 1 eq) 1,5,7-Triazabicyclo[440]dec-5-ene (0.03 g, 0.2 mmol, 0.3 eq)and 2-amino-5-bromopyridine (0.44 g, 2.5 mmol, 4 eq) were added in avessel that was sealed with a septum and placed into the microwavecavity. Microwave irradiation (maximum emitted power 230 W) was used toincrease the temperature to 130° C. The reaction mixture was then keptat this temperature for 30 min. Then the residue was diluted with DCMand washed with NaHCO₃ saturated solution. The organic phase wasseparated, dried over Na₂SO₄ and concentrated in vacuo. The crude waspurified by silica gel chromatography (cHex/AcOEt gradient) to give thetitle compound (0.03 g, 15%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.29-8.23 (m, 1H), 8.18-8.09 (m, 2H),7.98 (s, 1H), 7.83-7.74 (m, 1H), 6.90-6.82 (m, 1H), 6.72 (s, 1H), 3.93(s, 3H), 3.43 (t, J=7.5 Hz, 1H), 2.22-2.07 (m, 1H), 1.88-1.74 (m, 1H),1.41-1.21 (m, 2H), 0.93 (t, J=7.3, 1.5 Hz, 3H).

C₁₆H₁₅BrN₃O₂, Calculated [364.24]. found [M+H⁺], Br pattern 364-366,RT=1.65 (method f).

Example 15 2-(2-Methoxy-pyridin-4-yl)-pentanoic acid(5-chloro-thiazol-2-yl)-amide

2-(2-Methoxy-pyridin-4-yl)-pentanoic acid

The title compound was synthesized following the general procedure D3starting from 2-(2-methoxy-pyridin-4-yl)-pentanoic acid ethyl ester.(1.50 g, 79%).

Mass (calculated) C₁₁H₁₅NO₃ [209]; (found) [M+H⁺]=210.

Synthesis of 2-(2-Methoxy-pyridin-4-yl)-pentanoic acid(5-chloro-thiazol-2-yl)-amide

The title compound was synthesized following the general procedure E1starting from 2-(2-methoxy-pyridin-4-yl)-pentanoic acid and5-chloro-thiazol-2-ylamine (0.04 g, y 16%).

¹H NMR (400 MHz, Chloroform-d3) δ 10.11 (bp, 1H), 8.14 (d, J=5.4 Hz,1H), 7.23 (s, 1H), 6.86 (dd, J=5.4, 1.4 Hz, 1H), 6.72 (d, J=1.4 Hz, 1H),3.94 (s, 3H), 3.56 (t, J=7.5 Hz, 1H), 2.29-2.04 (m, 1H), 1.95-1.66 (m,1H), 1.43-1.19 (m, 2H), 0.94 (t, J=7.3 Hz, 3H). C₁₄H₁₆N₃O₂SCl,Calculated [325.81]. found [M+H⁺], 326, RT=2.01 (method e).

Example 16 2-(6-Chloro-pyridin-3-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

(6-Chloro-pyridin-3-yl)-acetic acid ethyl ester

To a solution of EtOH (27 mL), concentrated H2SO₄ (10 mL) was addeddropwise and 2-chloropyridine-5-acetonitrile (2.00 g, 13.1 mmol) wasadded portionwise. The solution was stirred at 100° C. for three hours.The mixture was added dropwise to a solution of NaHCO₃ (30.00 g) in H₂O(100 mL) and it was extracted twice with DCM. The organic layer werecollected, dried and evaporated to give the title compound (2.60 g,quant.)

C₉H10ClNO₂ Mass (calculated) [199]; (found) [M+H]⁺=200.

2-(6-Chloro-pyridin-3-yl)-pentanoic acid ethyl ester

The title compound was obtained following general procedure B1 foralkylation and starting from (6-chloro-pyridin-3-yl)-acetic acid ethylester (0.72 g, 45%).

Cl₂H16ClNO₂ Mass (calculated) [241]; (found) [M+H]⁺=242.

2-(6-Chloro-pyridin-3-yl)-pentanoic acid

2-(6-Chloro-pyridin-3-yl)-pentanoic acid ethyl ester (0.72 g, 2.96 mmol)was dissolved in concentrated HCl (8 mL) and the solution was stirred at100° C. for two hours. The mixture was concentrated under reducepressure and the crude product was used in the next step without furtherpurification (1.00 g, quant.).

C₁₀H₁₂ClNO₂ Mass (calculated) [213]; (found) [M+H]⁺=214.

2-(6-Chloro-pyridin-3-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide

The title compound was obtained following general procedure E1 for amidecoupling and starting from 2-(6-Chloro-pyridin-3-yl)-pentanoic acid and5-bromo-pyridin-2-ylamine, (0.12 g, 65%).

C₁₅H₁₅BrClN₃O Mass (calculated) [368]; (found) [M+H]⁺=370.

Example 172-(5-Bromo-pyridin-3-yl)-N-(5-bromo-pyridin-2-yl)-3-(5-trifluoromethyl-furan-2-yl)-propionamide

2-(5-Bromo-pyridin-3-yl)-3-(5-trifluoromethyl-furan-2-yl)-propionic acidethyl ester

The title compound was obtained starting from(5-bromo-pyridin-3-yl)-acetic acid ethyl ester and2-bromomethyl-5-methyl-furan following general procedure B1 foralkylation (0.33 g, 72%).

C₁₅H₁₃BrF₃NO₃ Mass (calculated) [392]. found [M+1] 392-394 brominepattern.

2-(5-Bromo-pyridin-3-yl)-3-(5-trifluoromethyl-furan-2-yl)-propionic acid

The title compound was obtained using general procedure D3 for esterhydrolysis and starting from2-(5-bromo-pyridin-3-yl)-3-(5-trifluoromethyl-furan-2-yl)-propionic acidethyl ester (0.30 g, quant.).

C₁₃H9BrF₃NO₃ Mass (calculated) [364]. found [M+1] 364-366 brominepattern.

2-(5-Bromo-pyridin-3-yl)-N-(5-bromo-pyridin-2-yl)-3-(5-trifluoromethyl-furan-2-yl)-propionamide

Acid (0.06 g, 0.165 mmol, 1 eq) and 5-bromo-2-aminopyrdine (0.029 g,0.165 mmol, 1 eq) were dissolved in AcOEt (2 mL), DIPEA (0.057 mL, 0.33mmol, 2 eq) were added and solution cooled to 0° C. T3P 50% solution inAcOEt (0.127 mL, 0.33 mmol, 1.5 eq) was added and reaction was stirredfor 12 h at room temperature. NaHCO₃ saturated solution (2 mL) wasadded; organic layer was separated, dried over Na₂SO₄, filtered andevaporated. The crude product was purified by silica gel chromatography(cHex/0-35% AcOEt) to give the title compound (0.08 g, 78%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.63 (d, J=2.2 Hz, 1H), 8.45 (d, J=2.0Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.12 (d, J=8.9 Hz, 1H), 7.97 (bs, 1H),7.92 (t, J=2.0 Hz, 1H), 7.82 (dd, J=8.8, 2.4 Hz, 1H), 6.63 (d, J=3.3,1H), 6.09 (d, J=3.3 Hz, 1H), 3.95 (t, J=7.7 Hz, 1H), 3.59 (m, 1H), 3.17(m, 1H).

C₁₅H₁₂N₃O₂F3Br₂, Calculated [519.11]. found [M+H⁺], 520, RT=1.81 (methodf).

Example 18 2-(6-Methoxy-pyridin-3-yl)-pentatonic acid(5-bromo-pyridin-2-yl)-amide

Cyano-(6-methoxy-pyridin-3-yl)-acetic acid ethyl ester

Ethyl cyanoacetate (0.938 mL, 8.8 mmol, 1 eq) and5-bromo-2-methoxy-pyridine (1.3 mL, 10 mmol, 1.2 eq) were added to asuspension of potassium tert-butoxide (2.4 g, 21.4 mmol, 2.5 eq) in1,4-dioxane (25 mL) dry under N2 atmosphere. A solution of palladiumacetate (0.039 g, 0.17 mmol, 0.02 eq) and Qphos (0.198 g, 0.39 mmol,0.04 eq) in 1,4-dioxane (10 mL) dry was added dropwise to reactionmixture. The reaction was heated at 70° C. for 2 h before cooling toroom temperature; 1N acetic acid solution (15 mL) and AcOEt (20 mL) wereadded, organic layer was collected, dried over Na₂SO₄ and evaporated.The crude product was purified by silica gel chromatography with (cHex−10% AcOEt) to give the title compound (1.13 g, 60%).

C₁₁H₁₂N₂O₃ Mass (calculated) [220]; (found) [M+H]⁺=221.

2-Cyano-2-(6-methoxy-pyridin-3-yl)-pentanoic acid ethyl ester

Cyano-(6-methoxy-pyridin-3-yl)-acetic acid ethyl ester (1.13 g, 5.1mmol, 1 eq) was dissolved in dimethylformamide (10 mL), cesium carbonate(2 g, 6.12 mmol, 1.2 eq) and 1-iodo-propane (0.55 mL, 5.6 mmol, 1.1 eq)were added and the mixture was stirred at room temperature overnight.H₂O (500 mL) was added and crude extracted three times with AcOEt (3×100mL). Organic phases were combined, dried over Na₂SO₄ and concentrated invacuo. The crude product was purified by silica gel chromatography(cHex-10% AcOEt) to give the title compound (1 g, 74%).

C₁₄H₁₈N203 Mass (calculated) [262]; (found) [M+H]⁺=263.

2-(6-Methoxy-pyridin-3-yl)-pentanoic acid

2-cyano-2-(6-methoxy-pyridin-3-yl)-pentanoic acid ethyl ester (1 g, 3.8mmol, 1 eq) was dissolved in methanol (7.5 mL) NaOH 2N solution (7.5 mL,15 mmol, 4 eq) was added and mixture was stirred one hour at roomtemperature and at 60° C. for 2 hours. The reaction mixture wasacidified to pH=5 with HCl 1 N and extracted with AcOEt (3×20 ml).Organic layers were collected, dried over Na₂SO₄ and concentrated invacuo. The crude product was purified by silica gel chromatography(cHex-33% AcOEt) to give the title compound (0.65 g, 82%).

C₁₁H₁₅NO₃ Mass (calculated) [209]; (found) [M+H]⁺=210.

2-(6-Methoxy-pyridin-3-yl)-pentatonic acid (5-bromo-pyridin-2-yl)-amide

The amide coupling was performed using general procedure Elto give thetitle compound (0.01 g, 5%).

¹H NMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 8.26 (d, J=2.5 Hz, 1H),8.22-8.11 (m, 2H), 7.79 (dd, J=8.9, 2.5 Hz, 1H), 7.72 (dd, J=8.7, 2.6Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 3.97 (s, 3H), 3.58 (t, J=7.7 Hz, 1H),2.21-2.10 (m, 1H), 1.92-1.65 (m, 1H), 1.49-1.15 (m, 2H), 0.93 (t, J=7.3Hz, 3H).

C₁₆H₁₈N₃O₂Br, Calculated [364.24]. found [M+H⁺], Br pattern 364-366,RT=1.67 (method f).

Example 19 2-(5-Bromo-2,3-dihydro-indol-1-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

2-Bromo-pentanoic acid (5-bromo-pyridin-2-yl)-amide

2-Bromopentanoic acid (2.17 mL, 16.57 mmol, 1 eq) was dissolved indichloroethane (15 mL) solution was reach to 0° C., Oxalyl chloride(2.90 mL, 33.15 mmol, 2 eq) was added follow by 1 drop of DMF andreaction was stirred at room temperature for 5 h. Solution wasevaporated to dryness. Acyl chloride was dissolved in dichloroethane (15mL) and slowly added to a solution of 5-bromo-2-aminopyridine (3.1 g,18.23 mmol, 1.1 eq) and DIPEA (5.78 mL, 33.15 mmol, 2 eq) indichloroethane over a period of 10 minutes; reaction was stirred at roomtemperature for 1 h. NaHCO₃ saturated solution was added, organic phasewas collected, washed with a saturated solution of NaCl, dried overNa₂SO4, filtered and evaporated. The crude product was purified bysilica gel chromatography (cHex-5% AcOEt) to give the title compound(3.3 g, 65%).

C₁₀H₁₂Br₂N₂O Mass (calculated) [336]. found [M+1]=336-338 brominepattern.

2-(5-Bromo-2,3-dihydro-indol-1-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

2-Bromo-pentanoic acid (5-bromo-pyridin-2-yl)-amide (0.13 g, 0.39 mmol,1 eq) was dissolved in CH₃CN (2 mL), DIPEA (0.081 mL, 0.46 mmol, 1.2 eq)and 5-bromoindoline (0.087 mL, 0.46 mmol, 1.2 eq) were added. Reactionwas heated at 70° C. for 16 h. Acetonitrile was evaporated, the cruderesidue was partitioned in AcOEt (2 mL) and H₂O (2 mL), organic phasewas collected, dried over Na₂SO₄, filtered and evaporated. The crudeproduct was purified by reverse phase chromatography to give the titlecompound (0.021 g, 12%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.97 (s, 1H), 8.29 (d, J=2.5 Hz, 1H),8.21 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8, 2.5 Hz, 1H), 7.22 (d, J=2.0 Hz,1H), 7.14 (dd, J=8.4, 2.0 Hz, 1H), 6.33 (d, J=8.4 Hz, 1H), 3.95 (dd,J=7.5, 6.4 Hz, 1H), 3.62-3.43 (m, 2H), 3.16-2.97 (m, 2H), 2.23-2.00 (m,1H), 1.79 (m, 1H), 1.55-1.29 (m, 2H), 0.96 (t, J=7.3 Hz, 3H).

C₁₅H₁₉N₃OBr₂, Calculated [453.17]. found [M+H⁺], 2Br pattern 454,RT=2.12 (method f).

Example 20 2-(5-Bromo-3-methyl-indol-1-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

2-(5-Bromo-3-methyl-indol-1-yl)-pentanoic acid ethyl ester

To a solution of 5-bromo-3-methyl-1H-indole (0.50 g, 2.38 mmol) in DMF(4 mL), NaH (60% in mineral oil, 0.11 g, 2.85 mmol) was added and themixture was stirred at room temperature for 30 minutes.2-Bromo-pentanoic acid ethyl ester (0.45 mL, 2.62 mmol) was added andthe reaction was left stirring at room temperature overnight. SaturatedNaCl solution was added and the mixture was extracted with DCM. Theorganic phase was collected, dried over Na₂SO₄ and concentrated underreduced pressure. The crude product was purified by silica gelchromatography (cHex/AcOEt 80/20) to afford the title compound (0.35 g,46%).

C₁₆H₂₀BrNO₂ Mass (calculated) [338]; (found) [M+H]⁺=340.

2-(5-Bromo-3-methyl-indol-1-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

The title compound was obtained following general procedure F1 for amidecoupling and starting from 2-(5-bromo-3-methyl-indol-1-yl)-pentanoicacid ethyl ester and 5-bromo-pyridin-2-ylamine (0.08 g, 34%).

¹H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J=2.4 Hz, 1H), 8.15 (d, J=8.9Hz, 1H), 7.79 (dd, J=8.9, 2.4 Hz, 1H), 7.76-7.71 (m, 2H), 7.32 (dd,J=8.7, 1.9 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 7.01 (s, 1H), 4.90 (dd,J=10.7, 4.7 Hz, 1H), 2.48-2.36 (m, 1H), 2.34 (s, 3H), 2.23-2.07 (m, 1H),1.33-1.12 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

C₁₉H₁₉Br₂N₃O, Calculated [465.18]. found [M+H⁺], 2Br pattern, 466,RT=5.38 (method c).

Example 21 2-(3-Bromo-pyrrol-1-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

2-(3-Bromo-pyrrol-1-yl)-pentanoic acid ethyl ester

To a solution of 3-bromo-1-triisopropylsilanyl-1H-pyrrole (1.10 g, 3.64mmol) in THF (11 mL), a solution of tetrabutyl ammonium fluoride in THF(1M, 3.82 mL, 3.82 mmol) was added and reaction was stirred for 10minutes at room temperature. 5 mL of diethyl ether were added and themixture was washed with 10 mL of H₂O. The organic phase was collected,dried over Na₂SO₄ and concentrated under reduced pressure, obtaining3-bromo-1H-pyrrole that was used without further purification. To asuspension of NaH (60% in mineral oil, 0.10 g, 4.11 mL) in THF (9 mL),under nitrogen atmosphere, a solution of 3-bromo-1H-pyrrole (0.50 g,3.46 mmol) was added and the mixture was left stirring at roomtemperature for 1 hour. Then the reaction was cooled down to 0° C. and asolution of 2-bromo-pentanoic acid ethyl ester (0.86 g, 4.11 mmol) inDMF (9 mL) was added. The reaction was allowed to warm up to roomtemperature and was left stirring for 3 hours. Then H₂O was added (10mL) and the mixture was extracted with AcOEt (10 mL), the organic phasewas collected, dried over Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by silica gel chromatography(cHex/AcOEt 95/5) to afford the title compound (0.45 g, 60%).

C₁₁H₁₆BrNO₂ Mass (calculated) [274]; (found) [M+H]⁺=276.

2-(3-Bromo-pyrrol-1-yl)-pentanoic acid (5-bromo-pyridin-2-yl)-amide

The title compound was obtained following the general procedure F1 foramide coupling and starting from 2-(3-bromo-pyrrol-1-yl)-pentanoic acidethyl ester and 5-bromo-pyridin-2-ylamine (0.06 g, 32%).

¹H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.45 (t, J=1.5 Hz, 1H),8.04-7.98 (m, 2H), 6.97 (t, J=2.0 Hz, 1H), 6.86 (t, J=2.7 Hz, 1H), 6.08(dd, J=2.7, 2.0 Hz, 1H), 4.91 (dd, J=8.9, 6.5 Hz, 1H), 2.06-1.85 (m,2H), 1.22-1.08 (m, 2H), 0.87 (t, J=7.4 Hz, 3H).

C₁₄H₁₅Br₂N₃O, Calculated [401.10]. found [M+H⁺], 2 Br pattern, 402,RT=1.87 (method f).

Example 22 2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid ethyl ester

A suspension of 4-bromo-3-trifluoromethyl-1H-pyrazole (0.74 g, 3.44mmol) and K₂CO₃ (0.95 g, 6.88 mmol) in acetone (16 mL) was heated at 55°C. for 10 minutes and then was allowed to cool down to room temperature.2-Bromo-pentanoic acid ethyl ester (0.79 g, 3.78 mmol) was the added andthe mixture was heated at 55° C. for 18 hours. The solvent was removedunder reduced pressure and the residue was suspended in DCM and washedwith H₂O. The organic phase was collected, dried over Na₂SO₄ andconcentrated under reduced pressure to afford the title compound (1.38g, quant.).

C₁₁H₁₄BrF₃N₂O₂ Mass (calculated) [343]; (found) [M+H]⁺=345.

2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

The title compound was prepared following general procedure F1 for amidecoupling and starting from2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid ethyl esterand 5-bromo-pyrazin-2-ylamine (0.02 g, 15%).

¹H NMR (400 MHz, Chloroform-d3) δ 9.26 (s, 1H), 8.79 (s, 1H), 8.38 (s,1H), 7.71 (s, 1H), 4.92 (t, J=7.7 Hz, 1H), 2.25 (q, J=7.7 Hz, 2H),1.43-1.23 (m, 2H), 0.99 (t, J=7.5 Hz 3H). C₁₃H₁₂Br₂F3N₅O, Calculated[471.07]. found [M+H⁺], 2Br pattern, 472. RT=1.81 (method f).

Example 23 2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid(5-bromo-thiazol-2-yl)-amide

2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid

The title compound was prepared following general procedure D3 for esterhydrolysis and starting form2-[4-(4-Methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pentanoic acidethyl ester (0.50 g, quant.).

C₉H₁₀BrF₃N₂O₂ Mass (calculated) [316]; (found) [M+H]⁺=318.

2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid(5-bromo-thiazol-2-yl)-amide

To a solution of triphenylphosphine (0.20 g, 0.76 mmol) in DCM (2 ml)cooled at 0° C., N-bromosuccinimide (0.14 g; 0.76 mmol) was added andthe mixture left at 0° C. for minutes.2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid (0.15 g, 0.48mmol) was added and the reaction was allowed to warm up to roomtemperature and lest stirring for 45 minutes. 5-Bromo-thiazol-2-ylamine(0.31 g, 1.19 mmol) was added and the mixture was left stirring for 18hours at room temperature. The mixture was washed with 1N HCl solutionand NaHCO₃ saturated solution. The organic phase was collected and thesolvent was removed under reduced pressure. The crude product waspurified by silica gel chromatography (cHex/AcOEt 3/1), to afford thetitle compound (0.07 g, 40%).

¹H NMR (400 MHz, Chloroform-d3) δ 10.41 (s, 1H), 7.72 (s, 1H), 7.49 (s,1H), 4.98 (dd, J=8.7, 6.8 Hz, 1H), 2.32-2.14 (m, 2H), 1.46-1.20 (m, 2H),0.98 (t, J=7.3 Hz, 3H).

C₁₂H₁₁Br₂F3N₄OS, Calculated [476.11]. found [M+H⁺], 2 Br pattern, 477RT=1.90 (method f).

Example 24 2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid(3-tert-butyl-isoxazol-5-yl)-amide

The title compound was obtained following general procedure E1 for amidecoupling and starting from2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid and3-tert-Butyl-isoxazol-5-ylamine (0.02 g, 15%).

¹H NMR (400 MHz, Chloroform-d3) δ 9.15 (s, 1H), 7.68 (s, 1H), 6.29 (s,1H), 4.94-4.85 (m, 1H), 2.29-2.14 (m, 2H), 1.42-1.23 (m, 11H), 0.98 (t,J=7.3 Hz, 3H).

C₁₆H20N402F3Br, Calculated [437.25]. found [M+H⁺], Br pattern, 437-439,RT=1.90 (method f).

Example 25 2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-pentanoic acid ethyl ester

Diethyl propyl malonate (1.0 g, 4.95 mmol, 1 eq) andN-hydroxy-benzamidine (0.337 g, 2.48 mmol, 0.5 eq) were mixed in apressure tube and heated at 140° C. for 24 h. After cooling reaction,the crude residue was dissolved in AcOEt (5 mL) and purified by silicagel chromatography (cHex-50% AcOEt) to give the title compound (0.35 g,50%).

C₁₅H₁₈N₂O₃ Mass (calculated) [274.32]; (found) [M+H]⁺=275.25.

2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-pentanoic acid

The title compound was obtained following general procedure D3 for esterhydrolysis and starting from2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-pentanoic acid ethyl ester, the crudeproduct was purified by silica gel chromatography (cHex 20% AcOEt) togive the title compound (0.11 g, 30%).

C₁₃H₁₄N₂O₃ Mass (calculated) [246.27]; (found) [M−H]⁻=245.3.

2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-pentanoic acid (0.11 g, 0.44 mmol, 1eq) was dissolved in DCM (2 mL), CDI (0.798 g, 0.49 mmol, 1.1 eq) wasadded and reaction was stirred for 1 h at room temperature.5-Bromo-2-aminopyridine (0.77 g, 0.44 mmol, 1 eq) was added and reactionwas stirred for 16 h. NaOH 1N solution in H₂O (2 mL) was added; organicphase was collected, dried over Na₂SO₄ and concentrated under vacuo. Thecrude product was purified by preparative HPLC to give the titlecompound (0.031 g, 20%).

¹H NMR (400 MHz, Chloroform-d3) δ 9.35 (s, 1H), 8.37 (d, J=2.4 Hz, 1H),8.20-8.06 (m, 3H), 7.82 (dd, J=8.9, 2.4 Hz, 1H), 7.60-7.48 (m, 3H), 4.13(t, J=7.4 Hz, 1H), 2.35-2.16 (m, 2H), 1.52-1.38 (m, 2H), 0.99 (t, J=7.3Hz, 3H).

C₁₅7N402Br, Calculated [401.26]. found [M+H⁺], Br pattern 401-403,RT=1.88 (method f).

Example 26 2-(2-Difluoromethoxy-pyridin-4-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide

2-(2-oxo-1,2-dihydro-pyridin-4-yl)-pentanoic acid ethyl ester

2-(2-Methoxy-pyridin-4-yl)-pentanoic acid ethyl ester (1.0 g, 4.2 mmol,1.0 eq.) was dissolved in acetonitrile (12 mL) at 20° C. andiodo-trimethylsilane (1.26 mL, 8.8 mmol, 2.1 eq.) was added dropwise.The mixture was heated to 80° C. for 12 h and then cooled at roomtemperature. The solvent was concentrated under reduced pressure and thecrude product was purified by silica gel chromatography (AcOEt: cHex1:9) to afford the title compound (0.6 g, 58%).

C₁₂H₁₇NO₃ mass (calculated) [222]; (found) [M+H]⁺=223 m/z.

2-(2-difluoromethoxy-pyridin-4-yl)-pentanoic acid ethyl ester

2-(2-oxo-1,2-dihydro-pyridin-4-yl)-pentanoic acid ethyl ester (0.50 g,2.2 mmol, 1.0 eq.) was dissolved in CH₃CN (10 mL) at 20° C. and sodiumchloro-difluoroacetate (0.41 g, 2.7 mmol, 1.2 eq.) was addedportionwise. The reaction was heated at 100° C. for 12 h and then cooledto room temperature. The solvent was distilled under reduced pressureand the crude product was purified by silica gel chromatography(AcOEt:cHex 1:9) to give the title compound (0.26 g, 42%).

C₁₃H₁₇F2NO₃ mass (calculated) [273]; (found) [M+H]⁺=274 m/z.

2-(2-difluoromethoxy-pyridin-4-yl)-pentanoic acid5-(2-Br-pyridin-2-yl)-amide 2-(2-difluoromethoxy-pyridin-4-yl)-pentanoicacid ethyl ester (190 mg, 0.70 mmol, 1 eq.),1,5,7-Triazabicyclo[4.4.0]dec-5-ene (30 mg, 0.22 mmol, 0.3 eq.) and5-bromo-pyridin-2-yl amine (691 mg, 4 mmol, 5.7 eq.) were respectivelytransferred in the micro-wave tube and 2 micro-wave cycles wereperformed (T=130° C.; power=230 W; t=30 minutes). Then the reaction wascooled at room temperature and rinsed with dichloromethane. The organicsolution was washed with sodium bicarbonate saturated solution and H₂O.The organic layer was concentrated under reduced pressure and the crudeproduct was purified on silica gel chromatography (AcOEt:cHex 1:5) togive the title compound (0.036 g, 13%).

¹H NMR (400 MHz, Chloroform-d3) δ 8.29 (d, J=2.5 Hz, 1H), 8.18-8.11 (m,2H), 8.04 (s, 1H), 7.81 (dd, J=8.9, 2.5 Hz, 1H), 7.46 (t, J=73.0 Hz,1H), 7.11 (dd, J=5.3, 1.5 Hz, 1H), 6.90 (d, J=1.5 Hz, 1H), 3.48 (t,J=7.5 Hz, 1H), 2.23-2.09 (m, 1H), 1.89-1.75 (m, 1H), 1.45-1.19 (m, 2H),0.95 (t, J=7.3 Hz, 3H).

C₁₆H₁₆BrF₂N₃O₂, Calculated [400.2]. found [M+H⁺], Br pattern, 400-402,RT=2.06 (method d).

Example 27 2-(2-Difluoromethoxy-pyridin-4-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

2-(2-difluoromethoxy-pyridin-4-yl)-pentanoic acid ethyl ester (200 mg,0.73 mmol, 1 eq.), 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (30 mg, 0.22mmol, 0.3 eq.) and 5-bromo-pyrazine-2-yl amine (690 mg, 4 mmol, 5.7 eq.)were respectively transferred in the micro-wave tube and 2 micro-wavecycles were performed (T=130° C.; power=230 W; t=30 minutes). Then thereaction was cooled at room temperature and rinsed with dichloromethane.The organic solution was washed with sodium bicarbonate saturatedsolution and H₂O. The organic layer was concentrated under reducedpressure and the crude product was purified on silica gel chromatography(AcOEt:cHex 1:5) to give the title compound (0.016 g, 7%).

¹H NMR (400 MHz, Chloroform-d3) δ 9.32 (d, J=1.4 Hz, 1H), 8.32 (d, J=1.6Hz, 1H), 8.18 (d, J=5.3 Hz, 1H), 7.77 (s, 1H), 7.38 (t, J=72.8 Hz, 1H),7.13 (dd, J=5.3, 1.6 Hz, 1H), 6.91 (d, J=1.4 Hz, 1H), 3.54 (t, J=7.5 Hz,1H), 2.25-2.11 (m, 1H), 1.92-1.78 (m, 1H), 1.46-1.23 (m, 2H), 0.96 (t,J=7.3 Hz, 3H).

C₁₅H₁₅N402F2Br, Calculated [401.21]. found [M+H⁺], Br pattern, 401-403,RT=2.17 (method e).

Example 28 22-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid(5-chloro-thiazol-2-yl)-amide

2-(6-Chloro-pyridin-3-yl)-pentanenitrile

The title compound was obtained starting from2-chloropyridine-5-acetonitrile that was treated in the same conditionsof general procedure B1 for alkylation (3.80 g, 58%).

2-[6-(1-Methyl-1H-pyrazol-3-yl)-pyridin-3-yl]pentanenitrile

The title compound was synthesized following the general procedure 0 forSuzuki coupling starting from 2-(6-chloro-pyridin-3-yl)-pentanenitrileand 1-methylpyrazole-4-boronic acid pinacol ester (3.80 g, 83%).

C₁₄H₁₆N4 Mass (calculated) [240]. found [M+H⁺]=241.

2-[6-(1-Methyl-1H-pyrazol-3-yl)-pyridin-3-yl]-pentanoic acid

The starting nitrile (3.8 g, 15.6 mmol, 1 eq) was dissolved in HCl 6Naqueous solution (40 mL), solution was heated at 100° C. for 12 h. H₂Owas evaporated; the solid crude product was triturated with diethylether, filtered off and dried to give the title compound (3.7 g, 97%).

C₁₄H₁₇N3O₂ Mass (calculated) [259]. found [M+H]⁺=260.

2-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-3-yl]pentanoic acid(5-bromo-thiazol-2-yl)-amide

The title compound was obtained following procedure E1 for amidecoupling with thionyl chloride after preparative HPLC purification (0.05g, 37%).

¹H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.23(s, 1H), 7.94 (s, 1H), 7.71 (dd, J=8.3, 2.3 Hz, 1H), 7.60 (d, J=8.2 Hz,1H), 7.50 (s, 1H), 3.90-3.81 (m, 4H), 2.11-1.97 (m, 1H), 1.80-1.66 (m,1H), 1.28-1.13 (m, 2H), 0.87 (t, J=7.3 Hz, 3H). C₁₇H₁₈N₅SCl, Calculated[375.88]. found [M+H⁺], 376, RT=1.28 (method f).

Example 292-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid(3-tert-butyl-isoxazol-5-yl)-amide

2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid tert-butyl ester

The title compound was obtained by alkylation of(6-chloro-5-cyano-pyridin-3-yl)-acetic acid tert-butyl ester wasperformed following the general procedure B1 (0.60 g, 60%). C₁₅H₁₉ClN₂O₂Mass (calculated) [294]; (found) [M+H⁺]=295.

2-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acidtert-butyl ester

The title compound was synthesized following the general procedure O forSuzuki coupling, starting from2-(6-chloro-5-cyano-pyridin-3-yl)-pentanoic acid tert-butyl ester and1-methylpyrazole-4-boronic acid pinacol ester. The crude was purified bysilica gel chromatography (cHex/AcOEt gradient) to give the titlecompound (0.25 g, 77%).

C₁₉H24N₄O₂ Mass (calculated) [340]; (found) [M+H⁺]=341.

2-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid

The title compound was synthesized following the general procedure D2starting from2-[5-cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acidtert-butyl ester (0.20 g, quant.).

C₁₅H16N₄O₂ Mass (calculated)=[284]. found [M+H⁺]=285.

2-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid(3-tert-butyl-isoxazol-5-yl)-amide

The title compound was synthesized following the general procedure E1starting from2-[5-cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid and3-tert-Butyl-isoxazol-5-ylamine (0.01 g, 26%).

¹H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.42(s, 1H), 8.20 (d, J=2.4 Hz, 1H), 8.11 (s, 1H), 6.23 (s, 1H), 3.92 (s,3H), 3.89-3.78 (m, 1H), 2.11-1.97 (m, 1H), 1.83-1.69 (m, 1H), 1.28-1.14(m, 11H), 0.87 (t, J=7.3 Hz, 3H).

C₂₂H26N602, Calculated [406.48]. found [M+H⁺], 407, RT=1.58 (method f).

Example 302-[4-(4-Methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

2-[4-(4-Methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]pentanoic acidethyl ester

The title compound was prepared following general procedure O for Suzukicoupling and starting from 4-bromo-3-trifluoromethyl-1H-pyrazole and4-methoxyphenyl boronic acid, after purification by silica gelchromatography (cHex/AcOEt 3/1) (0.09 g, 28%).

C₁₈H₂₁F₃N₂O₃ Mass (calculated) [370]; (found) [M+H]⁺=372.

2-[4-(4-Methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pentanoic acid(5-bromo-pyrazin-2-yl)-amide

The title compound was prepared following general procedure F1 for amidecoupling and starting from2-[4-(4-methoxy-phenyl)-3-trifluoromethyl-pyrazol-1-yl]-pentanoic acidethyl ester and 5-bromo-pyrazin-2-ylamine (0.01 g, 6%).

¹H NMR (400 MHz, Chloroform-d3) δ 9.29 (d, J=1.5 Hz, 1H), 9.21 (s, 1H),8.38 (d, J=1.5 Hz, 1H), 7.63 (s, 1H), 7.35 (d, J=8.7 Hz, 2H), 6.95 (d,J=8.7 Hz, 2H), 4.93 (dd, J=8.6, 6.7 Hz, 1H), 3.85 (s, 3H), 2.38-2.23 (m,2H), 1.42-1.28 (m, 2H), 1.00 (t, J=7.4 Hz, 3H). C₂₀H₁₉BrF₃N₅O₂,Calculated [498.30]. found [M−H⁺], Br pattern, 496-498, RT=1.87 (methodf).

Example 31 2,2-Dicyclohexyl-N-(6-methyl-pyridin-2-yl)-acetamide

The title compound was prepared following general procedure for E1 amidecoupling and starting from commercially available dicyclohexyl-aceticacid and N-(3-methyl-pyridin-2-yl)-amine (0.031 g, 8%).

1H NMR (400 MHz, cdcl3) δ 8.08 (d, J=8.3 Hz, 1H), 7.74 (s, 1H),7.63-7.52 (m, 1H), 6.88 (d, J=7.5 Hz, 1H), 2.44 (s, 3H), 1.93-1.56 (m,12H), 1.37-1.08 (m, 9H), 1.07-0.90 (m, 2H).

C₂₀H₃₀N₂O, Calculated [314,465]. found [M+H⁺] 315, RT=5.2 (method c).

Examples 32-151 listed in table 1 below were made according to themethod of column 3 and characterised by NMR (data not shown), andHPLC-MS (columns 5, 6, 7 and 8)

TABLE Synthesis Expected Retention Found MW Analytical Example Namemethod MW time (min) (M + 1) Purity method 322-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 368.66 1.71 370 96 fchloro-pyridin-2-yl)-amide Example 1 332-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 414.10 1.63 415 100 fbromo-pyrazin-2-yl)-amide Example 1 342-(5-Bromo-pyridin-3-yl)-pentanoic As in 427.13 1.87 428 90 f acid(5-bromo-6-methyl-pyridin-2-yl)-amide Example 1 352-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 374.68 1.73 376 97 fchloro-thiazol-2-yl)-amide Example 1 362-(5-Bromo-pyridin-3-yl)-pentanoic acid (6- As in 352.20 1.95 354 97 efluoro-pyridin-2-yl)-amide Example 1 372-(5-Bromo-pyridin-3-yl)-pentanoic acid (6- As in 413.11 2.16 413 93 ebromo-pyridin-2-yl)-amide Example 1 382-(5-Bromo-pyridin-3-yl)-pentanoic acid (3- As in 380.28 2.19 382 100 etert-butyl-isoxazol-5-yl)-amide Example 1 392-(6-Bromo-pyridin-2-yl)-pentanoic acid (5- As in 397.33 2.09 399 100 ebromo-thiazol-2-yl)-amide Example 1 402-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 358.23 1.58 359 98 ffluoro-thiazol-2-yl)-amide Example 1 412-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 475.24 2.6 476 98 ebromo-4-tert-butyl-thiazol-2-yl)-amide Example 1 422-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 433.16 1.82 434 98 fbromo-4-methyl-thiazol-2-yl)-amide Example 1 432-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 427.13 1.86 428 98 ebromo-3-methyl-pyridin-2-yl)-amide Example 1 442-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 419.14 2.15 420 95 ebromo-thiazol-2-yl)-amide Example 1 452-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 431.10 1.82 432 97 fbromo-6-fluoro-pyridin-2-yl)-amide Example 1 462-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 380.28 1.8 382 100 ftert-butyl-isoxazol-3-yl)-amide Example 1 472-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 402.21 1.77 404 97 ftrifluoromethyl-pyridin-2-yl)-amide Example 1 482-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 441.16 1.94 442 100 fbromo-4,6-dimethyl-pyridin-2-yl)-amide Example 1 492-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 427.13 1.82 428 100 fbromo-4-methyl-pyridin-2-yl)-amide Example 1 502-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 369.64 1.59 371 100 fchloro-pyrazin-2-yl)-amide Example 1 512-(5-Bromo-pyridin-3-yl)-pentanoic acid (3- As in 392.17 1.76 394 95 ftrifluoromethyl-isoxazol-5-yl)-amide Example 1 522-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic As in 386.65 2.07 387 100 dacid (5-chloro-pyridin-2-yl)-amide Example 10 532-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic As in 432.09 1.93 433 100 dacid (5-bromo-pyrazin-2-yl)-amide Example 10 542-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic As in 445.12 2.51 446 95 eacid (5-bromo-6-methyl-pyridin-2-yl)-amide Example 10 552-(6-Bromo-pyridin-2-yl)-pentanoic acid (5- As in 413.11 1.81 414 95 fbromo-pyridin-2-yl)-amide Example 12 562-(6-Bromo-pyridin-2-yl)-pentanoic acid (5- As in 419.14 1.76 420 95 fbromo-thiazol-2-yl)-amide Example 12 572-(2-Bromo-pyridin-4-yl)-pentanoic acid (5- As in 414.10 1.64 415 95 fbromo-pyrazin-2-yl)-amide Example 13 582-(2-Bromo-pyridin-4-yl)-pentanoic acid (5- As in 368.66 1.69 370 100 fchloro-pyridin-2-yl)-amide Example 13 592-(5-Bromo-pyridin-3-yl)-pentanoic acid (5- As in 352.20 1.55 354 100 ffluoro-pyridin-2-yl)-amide Example 13 602-(2-Methoxy-pyridin-4-yl)-pentanoic acid (5- As in 370.27 1.66 372 100f bromo-thiazol-2-yl)-amide Example 15 612-(2-Methoxy-pyridin-4-yl)-pentanoic acid (5- As in 365.23 1.88 365 97 ebromo-pyrazin-2-yl)-amide Example 15 622-(2-Methoxy-pyridin-4-yl)-pentanoic acid (3- As in 331.41 2.07 332 94 etert-butyl-isoxazol-5-yl)-amide Example 15 632-(2-Methoxy-pyridin-4-yl)-pentanoic acid (5- As in 378.26 2.23 378 95 ebromo-6-methyl-pyridin-2-yl)-amide Example 15 642-(6-Chloro-pyridin-3-yl)-pentanoic As in 324.20 1.68 324 95 f acid(5-chloro-pyridin-2-yl)-amide Example 16 652-(6-Chloro-pyridin-3-yl)-pentanoic acid (5- As in 325.19 1.85 325 95 echloro-pyrazin-2-yl)-amide Example 16 662-(5-Bromo-pyridin-3-yl)-N-(5-bromo- As in 520.10 1.73 521 100 fpyrazin-2-yl)-3-(5-trifluoromethyl-furan-2-yl)- Example 17 propionamide67 2-(5-Bromo-pyridin-3-yl)-N-(5-fluoro-pyridin- As in 458.20 1.67 458100 f 2-yl)-3-(5-trifluoromethyl-furan-2-yl)- Example 17 propionamide 682-(5-Bromo-pyridin-3-yl)-N-(5-chloro- As in 474.66 1.78 474 100 fpyridin-2-yl)-3-(5-trifluoromethyl-furan-2-yl)- Example 17 propionamide69 2-(5-Bromo-pyridin-3-yl)-N-(5-chloro- As in 475.65 1.7 475 100 fpyrazin-2-yl)-3-(5-trifluoromethyl-furan-2-yl)- Example 17 propionamide70 2-(6-Methoxy-pyridin-3-yl)-pentanoic acid (5- As in 370.27 1.67 372100 f bromo-thiazol-2-yl)-amide Example 18 712-(2-Methyl-pyridin-4-yl)-pentanoic acid (5- As in 354.27 1.07 356 95 fbromo-thiazol-2-yl)-amide Example 18 722-(3-Trifluoromethyl-pyrazol-1-yl)-pentanoic As in 391.19 1.77 393 100 facid (5-bromo-pyridin-2-yl)-amide Example 19 732-(4-Bromo-5-methyl-3-trifluoromethyl- As in 484.11 2 485 100 fpyrazol-1-yl)-pentanoic acid (5-bromo- Example 19 pyridin-2-yl)-amide 742-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 470.08 1.91 471 95 fpentanoic acid (5-bromo-pyridin-2-yl)-amide Example 19 752-(4-Bromo-3-cyano-pyrazol-1-yl)-pentanoic As in 427.09 1.74 428 100 facid (5-bromo-pyridin-2-yl)-amide Example 19 762-(5-Bromo-pyridin-3-yl)-hexanoic acid (5- As in 427.13 1.85 428 100 fbromo-pyridin-2-yl)-amide Example 2 77 2-(5-Bromo-pyridin-3-yl)-hexanoicacid (5- As in 382.68 1.81 384 100 f chloro-pyridin-2-yl)-amide Example2 78 2-(5-Bromo-pyridin-3-yl)-hexanoic acid (5- As in 428.12 1.2 429 100f bromo-pyrazin-2-yl)-amide Example 2 792-(5-Bromo-pyridin-3-yl)-hexanoic acid (3- As in 394.31 1.86 396 100 ftert-butyl-isoxazol-5-yl)-amide Example 2 802-(5-Bromo-pyridin-3-yl)-hexanoic acid (5- As in 445.12 1.92 446 100 fbromo-6-fluoro-pyridin-2-yl)-amide Example 2 812-(5-Bromo-pyridin-3-yl)-5-phenyl-pentanoic As in 445.74 1.81 446 98 facid (5-chloro-pyrazin-2-yl)-amide Example 2 822-(5-Bromo-pyridin-3-yl)-5-phenyl-pentanoic As in 489.20 1.91 489 90 facid (5-bromo-pyridin-2-yl)-amide Example 2 832-(5-Bromo-3-methyl-indol-1-yl)-pentanoic As in 420.73 5.28 421 95 cacid (5-chloro-pyridin-2-yl)-amide Example 20 842-(5-Bromo-3-methyl-indol-1-yl)-pentanoic As in 404.28 4.95 406 100 cacid (5-fluoro-pyridin-2-yl)-amide Example 20 852-(5-Bromo-indazol-1-yl)-pentanoic acid (5- As in 407.69 4.73 409 95 cchloro-pyridin-2-yl)-amide Example 20 862-(5-Bromo-pyrrolo[2,3-b]pyridin-1-yl)- As in 407.69 4.81 409 97 cpentanoic acid (5-chloro-pyridin-2-yl)-amide Example 20 872-(5-Bromo-pyrrolo[2,3-b]pyridin-1-yl)- As in 391.24 4.35 393 100 cpentanoic acid (5-fluoro-pyridin-2-yl)-amide Example 20 882-(3-Bromo-pyrrol-1-yl)-pentanoic acid (5- As in 356.65 1.84 358 100 fchloro-pyridin-2-yl)-amide Example 21 892-(3-Bromo-pyrrol-1-yl)-pentanoic acid (5- As in 402.08 1.78 403 100 fbromo-pyrazin-2-yl)-amide Example 21 902-(4-[4-methoxy-phenyl]-3-trifluoromethyl- As in 371.66 1.81 373 93 fpyrazol-1-yl)-pentanoic acid (5-bromo- Example 22 pyrazin-2-yl)-amide 912-(4-Bromo-3-methyl-pyrazol-1-yl)-pentanoic As in 417.10 1.74 418 100 facid (5-bromo-pyrazin-2-yl)-amide Example 22 922-(4-Bromo-imidazol-1-yl)-pentanoic acid (5- As in 402.08 1.79 402 100 fbromo-pyridin-2-yl)-amide Example 22 932-(4-Bromo-imidazol-1-yl)-pentanoic acid (5- As in 416.11 1.93 417 100 ebromo-6-methyl-pyridin-2-yl)-amide Example 22 942-[3-(4-Methoxy-phenyl)-pyrazol-1-yl]- As in 430.30 1.79 432 100 fpentanoic acid (5-bromo-pyrazin- Example 22 2-yl)-amide 952-(4-Bromo-3-tert-butyl-pyrazol-1-yl)- As in 459.18 2.09 460 91 fpentanoic acid (5-bromo-pyrazin-2-yl)-amide Example 22 962-(4-Bromo-3-cyano-pyrazol-1-yl)-pentanoic As in 428.08 1.67 427 100 facid (5-bromo-pyrazin-2-yl)-amide Example 22 972-(4-Bromo-3-propyl-pyrazol-1-yl)-pentanoic As in 445.15 1.97 444 98 facid (5-bromo-pyrazin-2-yl)-amide Example 22 982-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 409.18 1.79 409 100 fpentanoic acid (6-fluoro-pyridin-2-yl)-amide Example 22 992-(4-Chloro-3-trifluoromethyl-pyrazol-1-yl)- As in 426.62 1.8 428 92 fpentanoic acid (5-bromo-pyrazin-2-yl)-amide Example 22 1002-(4-Chloro-3-trifluoromethyl-pyrazol-1-yl)- As in 382.17 1.78 382 97 fpentanoic acid (5-chloro-pyrazin-2-yl)-amide Example 22 1012-(4-Chloro-3-trifluoromethyl-pyrazol-1-yl)- As in 425.63 1.88 427 98 fpentanoic acid (5-bromo-pyridin-2-yl)-amide Example 22 1022-(4-Chloro-3-trifluoromethyl-pyrazol-1-yl)- As in 381.18 1.85 381 95 fpentanoic acid (5-chloro-pyridin-2-yl)-amide Example 22 1032-(3-Bromo-pyrrol-1-yl)-pentanoic acid (3- As in 368.27 1.83 370 100 ftert-butyl-isoxazol-5-yl)-amide Example 23 1042-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 426.62 1.82 428 100 fpentanoic acid (5-chloro-pyrazin-2-yl)-amide Example 23 1052-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 409.18 1.76 411 100 fpentanoic acid (5-fluoro-pyridin-2-yl)-amide Example 23 1061-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 468.07 1.87 469 98 fcyclobutanecarboxylic acid (5-bromo-pyridin- Example 23 2-yl)-amide 1071-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 423.62 1.84 425 100 fcyclobutanecarboxylic acid (5-chloro-pyridin- Example 23 2-yl)-amide 1081-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 424.60 1.75 426 100 fcyclobutanecarboxylic acid (5-chloro-pyrazin- Example 23 2-yl)-amide 1091-(4-Chloro-3-trifluoromethyl-pyrazol-1-yl)- As in 424.60 1.77 424 95 fcyclobutanecarboxylic acid (5-bromo-pyrazin- Example 23 2-yl)-amide 1101-(4-Chloro-3-trifluoromethyl-pyrazol-1-yl)- As in 423.62 1.86 425 98 fcyclobutanecarboxylic acid (5-bromo-pyridin- Example 23 2-yl)-amide 1111-(4-Chloro-3-trifluoromethyl-pyrazol-1-yl)- As in 379.16 1.83 379 98 fcyclobutanecarboxylic acid (5-chloro-pyridin- Example 23 2-yl)-amide 1121-(4-Bromo-3-cyano-pyrazol-1-yl)- As in 425.08 1.69 424 95 fcyclobutanecarboxylic acid (5-bromo-pyridin- Example 23 2-yl)-amide 1132-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 425.63 1.86 427 100 fpentanoic acid (5-chloro-pyridin-2-yl)-amide Example 23 1142-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 426.62 1.78 428 98 fpentanoic acid (6-chloro-pyrimidin-4-yl)- Example 23 amide 1151-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 469.05 1.78 468 95 fcyclobutanecarboxylic acid (5-bromo-pyrazin- Example 23 2-yl)-amide 1161-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)- As in 407.16 1.73 409 95 fcyclobutanecarboxylic acid (5-fluoro-pyridin- Example 23 2-yl)-amide 1172-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-3- As in 428.33 1.4 430 99 fyl]-pentanoic acid (5-bromo-6-methyl-pyridin- Example 28 2-yl)-amide 1182-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)- As in 440.30 1.48 442 90 fpyridin-3-yl]-pentanoic acid (5-bromo- Example 29 pyrazin-2-yl)-amide119 2-[5-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)- As in 388.83 1.46 389 95 fpyridin-3-yl]-pentanoic acid (5-chloro- Example 29 pyrazin-2-yl)-amide120 2-[5-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)- As in 387.84 1.54 388 98 fpyridin-3-yl]-pentanoic acid (5-chloro-pyridin- Example 29 2-yl)-amide121 2-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)- As in 395.85 1.44 396 90 fpyridin-3-yl]-pentanoic acid (5-chloro- Example 29 pyrazin-2-yl)-amide122 2-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)- As in 378.40 1.4 379 95 fpyridin-3-yl]-pentanoic acid (5-fluoro-pyridin- Example 29 2-yl)-amide123 2-(5-Bromo-pyridin-3-yl)-N-(5-bromo- As in 413.11 1.9 414 100 dpyridin-2-yl)-3-methyl-butyramide Example 3 1242-(5-Bromo-pyridin-3-yl)-N-(5-chloro- As in 368.66 1.85 369 95 dpyridin-2-yl)-3-methyl-butyramide Example 3 1252-(5-Bromo-pyridin-3-yl)-N-(5-bromo- As in 414.10 1.77 415 100 dpyrazin-2-yl)3-methyl-butyramide Example 3 126N-(5-Bromo-3-methyl-pyridin-2-yl)-2-(5- As in 427.13 1.83 428 96 ebromo-pyridin-3-yl)-3-methyl-butyramide Example 3 1272-(5-Bromo-pyridin-3-yl)-N-(5-chloro-thiazol- As in 374.68 1.7 376 100 f2-yl)-3-methyl-butyramide Example 3 128N-(5-Bromo-3-fluoro-pyridin-2-yl)-2-(5- As in 431.10 1.5 432 97 fbromo-pyridin-3-yl)-3-methyl-butyramide Example 3 1292-(5-Bromo-pyridin-3-yl)-N-(3-tert-butyl- As in 380.28 1.78 382 100 fisoxazol-5-yl)-3-methyl-butyramide Example 3 130N-(5-Bromo-pyrazin-2-yl)-2,2-dicyclohexyl- As in 380.32 2.52 380-382 97d acetamide Example 31 131 N-(5-Bromo-thiazol-2-yl)-2,2-dicyclohexyl- Asin 385.36 2.6 385-387 96 d acetamide Example 31 1322,2-Dicyclohexyl-N-(5-fluoro-pyridin-2-yl)- As in 318.43 2.42 319 100 dacetamide Example 31 133 1-(5-Bromo-pyridin-3-yl)- As in 412.08 1.5 41393 f cyclobutanecarboxylic acid (5-bromo-pyrazin- Example 4 2-yl)-amide134 1-(5-Bromo-pyridin-3-yl)- As in 366.64 1.57 366 100 fcyclobutanecarboxylic acid (5-chloro-pyridin- Example 4 2-yl)-amid 1351-(5-Bromo-pyridin-3-yl)- As in 425.12 1.71 426 90 fcyclopentanecarboxylic acid (5-bromo- Example 5 pyridin-2-yl)-amide 1361-(5-Chloro-pyridin-3-yl)- As in 367.63 1.46 367 100 fcyclobutanecarboxylic acid (5-bromo-pyrazin- Example 6 2-yl)-amide 1371-(5-Chloro-pyridin-3-yl)- As in 366.64 1.57 364 95 fcyclobutanecarboxylic acid (5-bromo-pyridin- Example 6 2-yl)-amide 1382-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic As in 394.65 1.63 394 100 facid (5-bromo-pyrazin-2-yl)-amide Example 8 1392-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic As in 393.67 1.72 393 100 facid (5-bromo-pyridin-2-yl)-amide Example 8 1402-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic As in 349.21 1.69 349 100 facid (5-chloro-pyridin-2-yl)-amide Example 8 1412-(5-Chloro-pyridin-3-yl)-pentanoic acid (5- As in 369.64 1.83 369 95 fbromo-pyrazin-2-yl)amide Example 9 1422-(5-Chloro-pyridin-3-yl)-pentanoic acid (5- As in 325.19 1.58 323 95 fchloro-pyrazin-2-yl)-amide Example 9 1432-(5-Chloro-pyridin-3-yl)-pentanoic acid (5- As in 368.66 1.68 368 100 fbromo-pyridin-2-yl)-amide Example 9 1442-(5-Chloro-pyridin-3-yl)-pentanoic acid (5- As in 324.20 1.65 324 100 fchloro-pyridin-2-yl)-amide Example 9 1452-(6-Chloro-5-methyl-pyridin-3-yl)-pentanoic As in 339.22 1.65 339 95 facid (5-chloro-pyrazin-2-yl)-amide Example 9 1462-(6-Chloro-5-methyl-pyridin-3-yl)-pentanoic As in 383.67 1.68 383 100 facid (5-bromo-pyrazin-2-yl)-amide Example 9 1472-(6-Chloro-5-methyl-pyridin-3-yl)-pentanoic As in 338.23 1.72 338 100 facid (5-chloro-pyridin-2-yl)-amide Example 9 1482-(6-Chloro-5-methyl-pyridin-3-yl)-pentanoic As in 382.68 1.76 383 100 facid (5-bromo-pyridin-2-yl)-amide Example 9 1492-(2-Chloro-pyridin-4-yl)-pentanoic acid (5- As in 369.64 1.58 371 100 fbromo-pyrazin-2-yl)-amide Example 9 1502-(2-Chloro-pyridin-4-yl)-pentanoic acid (5- As in 324.20 1.64 324 100 fchloro-pyridin-2-yl)-amide Example 9 1512-(2-Chloro-pyridin-4-yl)-pentanoic acid (5- As in 368.66 1.67 368 100 fbromo-pyridin-2-yl)-amide Example 9

Biological Activity

Examples 1-151 were tested in the above described cellular againstCHO-S1P3 R1 cells, and show 1050 values ranging from 19 nM to 590 nM.

Example 33 was tested in the in vivo assays above described, at dosesranging 10 to 60 mg/kg showing anti-neuroinflammatory andneuroprotective activity (as et out in FIGS. 1-3) and improved cognitivefunctions (as set out in FIG. 4).

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1. A compound of formula (A),

wherein —R₁ is

X₁, X₆, X₇, X₉ and X₁₀ are halogen, C₁-C₄ linear branched or cyclicalkyl optionally substituted with one or more fluorine atoms; X₂, X₃,X₄, X₅ and X₈, are hydrogen, halogen, C₁-C₄ linear branched or cyclicalkyl optionally substituted with one or more fluorine atoms; with theproviso that at least one of X₂, X₃, X₄, and X₅ is not hydrogen R₂ is aC₃-C₆ linear branched or cyclic alkyl optionally substituted withphenyl, with one or more fluorine atoms or with trifluoromethyl-furanyl;R₂′ is hydrogen, F, C₁-C₃ linear or branched alkyl optionallysubstituted with one or more fluorine atoms; or R₂ and R₂′ together withthe carbon atom they are attached to form a C₃-C₆ cycloalkyl ring; —R₃is

Y₁ is halogen; Y₁′ is C₁-C₃ linear branched or cyclic alkyl optionallysubstituted with one or more fluorine atoms; Y₂ is cyano ormethoxyphenyl, C₁-C₃ linear branched or cyclic alkyl optionallysubstituted with one or more fluorine atoms; Y₃ is hydrogen, halogen ormethoxyphenyl; Y₄ is hydrogen, halogen, N-methylpyrazolyl or a C₁-C₃linear branched or cyclic alkoxy optionally substituted with one or morefluorine atoms, Y₅ is hydrogen halogen, cyano, or a C₁-C₃ linearbranched or cyclic alkyl optionally substituted with one or morefluorine atoms; with the proviso that at least one of Y₄ and Y₅ is nothydrogen; Y₆ is halogen, C₁-C₃ linear branched or cyclic alkyloptionally substituted with one or more fluorine atoms, or a C₁-C₃linear branched or cyclic alkoxy optionally substituted with one or morefluorine atoms; enantiomers, enantiomerically enriched mixtures, andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1wherein X₁ is halogen; X₂ is hydrogen, halogen or methyl; X₃ ishydrogen, halogen or trifluoromethyl; X₄ is hydrogen or methyl; X₅ ishydrogen or halogen; X₆ is halogen; with the proviso that at least oneof X₂, X₃, X₄, and X₅ is not hydrogen; X₇ is t-butyl or trifluoromethyl,preferably t-butyl; X₈ is hydrogen, methyl or t-butyl; X₉ is halogen;X₁₀ is t-butyl; R₂ is n-propyl, 3-phenyl-n-propyl, i-propyl, n-butyl,cyclohexyl, (5-trifluoromethyl-furan-2yl)-methyl; R₂′ is hydrogen, F,methyl; or R₂ and R₂′ together with the carbon atom they are attached toform a cyclobutyl or cyclopentyl group; Y₁ is halogen; Y₁′ is methyl; Y₂is methyl, n-propyl, cyano, trifluoromethyl or 4-methoxyphenyl; Y₃ ishydrogen, halogen, or 4-methoxyphenyl; Y₄ is hydrogen, halogen, methoxyor 1-methyl-pyrazol-4-yl; Y₅ is hydrogen, halogen, cyano or methyl; withthe proviso that at least one of Y₄ and Y₅ is not hydrogen; Y₆ halogen,methoxy or difluoromethoxy.
 3. The compound of claim 1, wherein —R₁ is

and wherein R₂, R₂′, R₃, X₁, X₂, X₃, X₄, X₅, X₈, X₉, Y₁, Y₁, Y₂, Y₃, Y₄,Y₅ and Y₆ are as defined in claim
 1. 4. The compound of claim 3, whichis selected from the group consisting of1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid(5-chloro-pyridin-2-yl)-amide;2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid(5-chloro-pyrazin-2-yl)-amide;2-(6-Chloro-5-fluoro-pyridin-3-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide; 2-(6-Bromo-pyridin-2-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide; 2-(2-Bromo-pyridin-4-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide; 2-(2-Methoxy-pyridin-4-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide; 2-(6-Methoxy-pyridin-3-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide;2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide;2-(2-Difluoromethoxy-pyridin-4-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide;2-[6-(1-Methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid(5-chloro-thiazol-2-yl)-amide; 2-(5-Bromo-pyridin-3-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide; 2-(5-Bromo-pyridin-3-yl)-pentanoic acid(5-bromo-3-methyl-pyridin-2-yl)-amide;2-(5-Bromo-pyridin-3-yl)-pentanoic acid(5-bromo-6-fluoro-pyridin-2-yl)-amide;2-(5-Bromo-pyridin-3-yl)-pentanoic acid (5-chloro-pyrazin-2-yl)-amide;2-(5-Bromo-pyridin-3-yl)-2-fluoro-pentanoic acid(5-chloro-pyridin-2-yl)-amide; 2-(2-Bromo-pyridin-4-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide; 2-(2-Bromo-pyridin-4-yl)-pentanoic acid(5-chloro-pyridin-2-yl)-amide; 2-(5-Bromo-pyridin-3-yl)-pentanoic acid(5-fluoro-pyridin-2-yl)-amide; 2-(2-Methoxy-pyridin-4-yl)-pentanoic acid(5-bromo-thiazol-2-yl)-amide; 2-(2-Methoxy-pyridin-4-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide;2-(4-Bromo-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide; 2-(4-Bromo-3-cyano-pyrazol-1-yl)-pentanoicacid (5-bromo-pyridin-2-yl)-amide; 2-(5-Bromo-pyridin-3-yl)-hexanoicacid (5-bromo-pyrazin-2-yl)-amide;2-(4-[4-methoxy-phenyl]-3-trifluoromethyl-pyrazol-1-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide;2-(4-Bromo-3-methyl-pyrazol-1-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide; 2-(4-Bromo-imidazol-1-yl)-pentanoic acid(5-bromo-pyridin-2-yl)-amide;2-[3-(4-Methoxy-phenyl)-pyrazol-1-yl]-pentanoic acid(5-bromo-pyrazin-2-yl)-amide; 2-(4-Bromo-3-cyano-pyrazol-1-yl)-pentanoicacid (5-bromo-pyrazin-2-yl)-amide;2-[5-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid(5-chloro-pyrazin-2-yl)-amide;2-[5-Cyano-6-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-pentanoic acid(5-chloro-pyrazin-2-yl)-amide;2-(5-Bromo-pyridin-3-yl)-N-(5-bromo-pyrazin-2-yl)3-methyl-butyramide;N-(5-Bromo-3-fluoro-pyridin-2-yl)-2-(5-bromo-pyridin-3-yl)-3-methyl-butyramide;N-(5-Bromo-pyrazin-2-yl)-2,2-dicyclohexyl-acetamide;1-(5-Bromo-pyridin-3-yl)-cyclobutanecarboxylic acid(5-bromo-pyrazin-2-yl)-amide;1-(5-Chloro-pyridin-3-yl)-cyclobutanecarboxylic acid(5-bromo-pyrazin-2-yl)-amide;2-(6-Chloro-5-cyano-pyridin-3-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)-amide; 2-(5-Chloro-pyridin-3-yl)-pentanoic acid(5-bromo-pyrazin-2-yl)amide; 2-(5-Chloro-pyridin-3-yl)-pentanoic acid(5-chloro-pyrazin-2-yl)-amide;2-(6-Chloro-5-methyl-pyridin-3-yl)-pentanoic acid(5-chloro-pyrazin-2-yl)-amide; and 2-(2-Chloro-pyridin-4-yl)-pentanoicacid (5-bromo-pyrazin-2-yl)-amide.
 5. The compound of claim 1 wherein—R₁ is

and wherein R₂, R₂′, R₃, X₇, Y₁, Y₁′, Y₂, Y₃, Y₄, Y₅ and Y₆ are asdefined in claim
 1. 6. The compound of claim 5, which is selected fromthe group consisting of 2-(5-Bromo-pyridin-3-yl)-pentanoic acid(3-tert-butyl-isoxazol-5-yl)-amide and 2-(5-Bromo-pyridin-3-yl)-hexanoicacid (3-tert-butyl-isoxazol-5-yl)-amide.
 7. The compound of claim 1,wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₂,Y₃, Y₄, Y₅ and Y₆ are as defined in claim
 1. 8. The compound of claim 3,wherein —R₃ is selected from

and wherein R₁, R₂, R₂′, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, Y₂,Y₃, Y₄, Y₅ and Y₆ are as defined in claim
 3. 9. A pharmaceuticalcomposition containing a compound according to claim
 1. 10. (canceled)11. A method of treating a disease selected from the group consisting ofarthritis, fibrosis, inflammatory syndromes, atherosclerosis, vasculardiseases, asthma, bradycardia, acute lung injury, lung inflammation,cancer, ocular hypertension, glaucoma, a neuroinflammatory disease, aneurodegenerative disease, Sandhoff's disease, kidneyischemia-reperfusion injury, pain, diabetic heart disease in a subjectin need thereof, said method comprising: administering to said subjectand effective amount of the medicament according to claim 9; andtreating said subject in need.
 12. The method according to claim 11,wherein said neurodegenerative disease is of selected from the groupconsisting of Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Huntington's disease and Multiple Sclerosis
 13. Themethod of claim 12, wherein said disease is Alzheimer's disease.